Methods of using cleavable drug conjugates and compositions thereof

ABSTRACT

Methods of synthesizing and using base-labile drug conjugates and compositions thereof are disclosed.

FIELD

The disclosure relates to multi-functional crosslinkers capable ofcoupling primary or secondary amine-containing therapeutic agents toligands. The multi-functional crosslinkers are cleavable upon exposureto esterases or to basic conditions to release the amine-containingtherapeutic agents. The disclosure also relates to conjugates comprisingthe crosslinkers, a therapeutic agent, and a ligand.

BACKGROUND

Drugs can often cause severe side effects and/or require multiple dosingregimens. Some of these side effects and inconvenient dosing regimenscan be controlled or reduced by the use of improved formulations and/orimproved delivery methods.

Paclitaxel, for example, is highly effective in treating breast and lungcancers by inhibiting the growth of cancer cells by binding tomicrotubules. However, because the drug has a low aqueous solubility,paclitaxel is typically formulated using the toxic solvent Cremophor® EL(polyoxyethylated castor oil), which limits the amount of drug that canbe administered to a patient. Patients taking the drug often requirepremedication with steroids or antihistamines for hypersensitivityreactions caused by the solvent.

Abraxane®, a new paclitaxel formulation, does not employ a toxicsolvent. When formulated with human serum albumin, the drug can besuspended in aqueous media. Thus, patients can better tolerate higherpaclitaxel doses (up to 260 m g/m² vs. 175 g/m²) and thereby achieve animproved response rate.

Doxorubicin is another highly effective cancer drug belonging to a classof anthracycline compounds. However, the drug can cause severecardiotoxicity and death. Patients taking a cumulative dose of 300 mg/m²have a 1-2% chance of developing cardiomyopathy, with the incidenceincreasing with increasing dose (400 mg/m², 3-5%; 450 mg/m², 5 to 8%;500 mg/m², 6-20%). The use of Doxil®, a pegylated liposomal formulationof doxorubicin, results in a reduced incidence of cardiotoxicity. Doxil®has a half-life in the blood of about 50 hours compared to about 10minutes for doxorubicin. The slow-release of doxorubicin may explain thelower toxicity of the Doxil® formulation. Myocet®, a non-pegylatedliposomal formulation of doxorubicin, also reduces the incidence ofcardiotoxicity. Furthermore, its use also reduces the incidence ofhand-foot syndrome associated with Doxil®. Myocet® is approved in Europeand is being evaluated in the United States.

Mitoxantrone is used for the treatment of acute non-lymphocyticleukemia. It is also indicated for reducing neurologic disability and/orthe frequency of clinical relapses in patients with secondary (chronic)progressive, progressive relapsing, or worsening relapsing-remittingmultiple sclerosis (MS). Although one of the most effective drugs fortreating MS, mitoxantrone is not recommended for long-term use. Patientswho exceed a cumulative dose of 140 mg/m² have an increased risk ofacquiring irreversible cardiotoxicity and death. There is no liposomalformulation of this drug.

Bleomycin, in combination with other chemotherapeutic agents, iseffective in treating squamous cell carcinoma, non-Hodgkin's lymphoma,and testicular carcinoma. However, patients taking a cumulative dose of400 units (˜400 mg) risk developing pulmonary fibrosis.

Mertansine, a derivative of maytansine, is an experimental cytotoxicagent. Because of its extreme toxicity, it is not used as a stand-alonetherapeutic agent. To minimize side effects and to maximize efficacy,the compound is conjugated to tumor-targeting monoclonal antibodies suchas lorvotuzumab and trastuzumab.

Vedotin, an auristatin, is another potent cytotoxic agent. To minimizeside effects and to maximize efficacy, it is conjugated totumor-targeting monoclonal antibody brentuximab.

Recombinant interferon alfa-2a (Roferon® A) is used for the treatment ofchronic hepatitis C, hairy cell leukemia, and chronic myelogenousleukemia. The recommended dosing regimen for Roferon® A for thetreatment of chronic hepatitis C is three times per week administeredsubcutaneously for 12 months.

Pegasys®, a pegylated formulation of interferon alfa-2a, requires lessfrequent dosing. The recommended dosing regimen for Pegasys® fortreating chronic hepatitis C is once weekly for 48 weeks by subcutaneousadministration.

Zalbin®, an interferon alfa-2b conjugated to human serum albumin, is analternative to unconjugated interferon alfa-2b (Intron® A). Instead ofsubcutaneously or intramuscularly dosing the non-conjugated drug threetimes a week for up to 24 months, Zalbin® is administered only onceevery two weeks.

Enfuvirtide, an FDA-approved HIV drug, is a fusion inhibitor having alinear 36-amino acid synthetic peptide. Due to its short half-life offour hours, treatment requires twice-daily subcutaneous injections. Thisinconvenient dosing schedule discourages its widespread use.

SUMMARY

Thus, there is a need for improved drug formulations that can reduce oreliminate severe side effects and enhance the tolerability, efficacy,and/or compliance of the drug. More specifically, many pharmacologicalcompounds having amine groups can benefit from conjugation to othermolecules or moieties provided that the crosslinking group is cleavablein vivo to release the drug. Thus, there is a need for new crosslinkershaving a functional group that can form a cleavable bond withamine-containing molecules upon exposure to esterases and/or under mildbasic conditions (e.g., pH 7.4 to 9) in vivo.

Cleavable cross-linkers, intermediates of cleavable cross-linkers,cleavable conjugates comprising the cleavable cross-linkers, and methodsof synthesizing the cross-linkers, intermediates, and conjugates aredisclosed. Therapeutic conjugates provided by the present disclosurecomprising the cleavable cross-linkers can reduce the side effects,enhance the efficacy, and/or improve the convenience of treatment forthe parent drug.

In a first aspect, compounds of Formula (II) are disclosed:

or a salt thereof, wherein:

each A¹ is independently selected from a thiol-reactive group, anamine-reactive group, an avidin-binding group, a photoreactive group, analkyne-reactive group, and an azide-reactive group;

each X¹ and X³ is independently selected from a covalent bond, C₁₋₂₀alkanediyl, substituted C₁₋₂₀ alkanediyl, C₁₋₂₀ heteroalkanediyl,substituted C₁₋₂₀ heteroalkanediyl, C₃₋₁₂ cycloalkanediyl, substitutedC₃₋₁₂ cycloalkanediyl, C₃₋₁₂ heterocycloalkanediyl, substituted C₃₋₁₂heterocycloalkanediyl, C₄₋₂₀ alkanecycloalkanediyl, substituted C₄₋₂₀alkanecycloalkanediyl, C₄₋₂₀ heteroalkanecycloalkanediyl, substitutedC₄₋₂₀ heteroalkanecycloalkanediyl, C₆₋₂₀ arenediyl, substituted C₆₋₂₀arenediyl, C₆₋₂₀ heteroarenediyl, substituted C₆₋₂₀ heteroarenediyl,C₇₋₂₀ alkanearenediyl, substituted C₇₋₂₀ alkanearenediyl, C₆₋₂₀heteroalkanearenediyl, substituted C₆₋₂₀ heteroalkanearenediyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein:

-   -   each n1 and n3 is independently an integer selected from 0 to 5;        and    -   each n2 is independently an integer selected from 1 to 25;

each X² is independently selected from a covalent bond, —O—, —S—, —N—,—N═, —N═N—, —N═C—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—, —C(O)N—,—C(O)S—, —C(O)N—N═, —OP(O)(OH)O—, —OC(O)O—, —OC(O)N—, —NC(O)N—, and—NC(S)N;

each R¹ and R² is independently selected from hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆ heteroalkyl,C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₆₋₁₀ heteroaryl, and substitutedC₆₋₁₀ heteroaryl;

D is selected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and

n5 is an integer selected from 1 to 20.

In a second aspect, compounds of Formula (III) are disclosed:

or a pharmaceutically acceptable salt thereof, wherein:

Q is selected from a ligand having at least one thiol group, a ligandhaving at least one primary amine group, a ligand having at least onesecondary amine group, ligand having at least one biotin-binding group,a ligand having at least one photoreactive group, a ligand having atleast one alkyne group, and a ligand having at least one azide group;

each Y is independently selected from a covalent bond and a hydrogenbond;

each A² is independently selected from a covalent bond, an amide group,an avidin-binding group, a carbamate group, a carbonyl group, adisulfide group, an ester group, a hydrazone group, an imine group, asuccinimide group, a sulfonamide group, a sulfone group, a sulfoxidegroup, a thioether group, a triazole group, and a urea group;

each X¹ and X³ is independently selected from a covalent bond, C₁₋₂₀alkanediyl, substituted C₁₋₂₀ alkanediyl, C₁₋₂₀ heteroalkanediyl,substituted C₁₋₂₀ heteroalkanediyl, C₃₋₁₂ cycloalkanediyl, substitutedC₃₋₁₂ cycloalkanediyl, C₃₋₁₂ heterocycloalkanediyl, substituted C₃₋₁₂heterocycloalkanediyl, C₄₋₂₀ alkanecycloalkanediyl, substituted C₄₋₂₀alkanecycloalkanediyl, C₄₋₂₀ heteroalkanecycloalkanediyl, substitutedC₄₋₂₀ heteroalkanecycloalkanediyl, C₆₋₂₀ arenediyl, substituted C₆₋₂₀arenediyl, C₆₋₂₀ heteroarenediyl, substituted C₆₋₂₀ heteroarenediyl,C₇₋₂₀ alkanearenediyl, substituted C₇₋₂₀ alkanearenediyl, C₆₋₂₀heteroalkanearenediyl, substituted C₆₋₂₀ heteroalkanearenediyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein:

-   -   each n1 and n3 is independently an integer selected from 0 to 5;        and    -   each n2 is independently an integer selected from 1 to 25;

each X² is independently selected from a covalent bond, —O—, —S—, —N—,—N═, —N═N—, —N═C—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—, —C(O)N—,—C(O)S—, —C(O)N—N═, —OP(O)(OH)O—, —OC(O)O—, —OC(O)N—, —NC(O)N—, and—NC(S)N;

each R¹ and R² is independently selected from hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆ heteroalkyl,C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₆₋₁₀ heteroaryl, and substitutedC₆₋₁₀ heteroaryl;

each D is independently selected from therapeutic agent having at leastone primary amine group, a therapeutic agent having at least onesecondary amine group, a therapeutic agent having at least one hydroxygroup, and a therapeutic agent having at least one thiol group; and

n6 is an integer selected from 1 to 20.

In a third aspect, pharmaceutical compositions are disclosed comprisinga compound of Formula (II), a compound of Formula (III), or apharmaceutically acceptable salt of any of the foregoing, and apharmaceutically acceptable carrier.

In a fourth aspect, methods of treating cancer, an autoimmune disease,or an infectious disease are disclosed, comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound of Formula (II), Formula (III), a pharmaceutical salt of anyof the foregoing, or a pharmaceutical composition comprising any one ofthe foregoing.

In a fifth aspect, methods of synthesizing compounds of Formula (I),Formula (II), and Formula (III), or a pharmaceutically acceptable saltof any of the foregoing are disclosed.

DETAILED DESCRIPTION Definitions

A dash (“—”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

Compounds provided by the present disclosure are encompassed bystructural formulae disclosed herein and include any specific compoundswithin these formulae. Compounds may be identified either by theirchemical structure and/or chemical name. When the chemical structure andchemical name conflict, the chemical structure is determinative of theidentity of the compound. The compounds described herein may contain oneor more chiral centers and/or double bonds and therefore, may exist asstereoisomers, such as double-bond isomers (i.e., geometric isomers),enantiomers or diastereomers. Accordingly, the chemical structuresdepicted herein encompass all possible enantiomers and stereoisomers ofthe illustrated compounds including the stereoisomerically pure form(e.g., geometrically pure, enantiomerically pure or diastereomericallypure) and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to one skilled in the art. The compounds may alsoexist in several tautomeric forms including the enol form, the keto formand mixtures thereof. Accordingly, the chemical structures depictedherein encompass all possible tautomeric forms of the illustratedcompounds. The compounds described also include isotopically labeledcompounds where one or more atoms have an atomic mass different from theatomic mass conventionally found in nature. Examples of isotopes thatmay be incorporated into the compounds disclosed herein include, but arenot limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Compounds mayexist in unsolvated forms as well as solvated forms, including hydratedforms and as N-oxides. Accordingly, compounds may be hydrated, solvated,or N-oxides. Certain compounds may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated herein and are intended to be within the scope of thepresent disclosure. Further, it should be understood, when partialstructures of the compounds are illustrated, that brackets indicate thepoint of attachment of the partial structure to the rest of themolecule.

The term “acyl” means an H—C(O)—, alkyl-C(O)—, or cycloalkyl-C(O)— groupwherein alkyl and cycloalkyl are as defined herein. In certainembodiments, an acyl group is C₁₋₈ acyl, C₁₋₆ acyl, C₁₋₄ acyl, and incertain embodiments, C₁₋₃ acyl.

The term “alkanearene” refers to a hydrocarbon group in which an alkylgroup is bonded to an aromatic group, wherein alkyl and aromatic groupare as defined herein. In certain embodiments, an alkanearene group isC₇₋₂₀ alkanearene, C₇₋₁₂ alkanearene, and in certain embodiments C₇₋₁₀alkanearenediyl.

The term “alkanearenediyl” refers to a diradical hydrocarbon groupderived by the removal of two hydrogen atoms from a single carbon atomor by the removal of a single hydrogen atom from two carbon atoms from aparent alkanearene group. In certain embodiments, an alkanearenediylgroup is C₇₋₂₀ alkanearenediyl, C₇₋₁₂ alkanearenediyl, and in certainembodiments C₇₋₁₀ alkanearenediyl.

The term “alkanediyl” refers to a diradical of a saturated orunsaturated, branched, or straight-chain acyclic hydrocarbon group,having, for example, from 1 to 20 carbon atoms, from 1-10 carbon atoms,from 1-6 carbon atoms, from 1 to 4 carbon atoms, or from 1 to 3hydrocarbon atoms. Examples of alkanediyl groups include methane-diyl(—CH₂—), ethane-1,2-diyl (—CH₂CH₂—), propane-1,3-diyl andiso-propane-1,2-diyl (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—),butane-1,4-diyl (—CH₂CH₂CH₂CH₂—), pentane-1,5-diyl (—CH₂CH₂CH₂CH₂CH₂—),hexane-1,6-diyl (—CH₂CH₂CH₂CH₂CH₂CH₂—), heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, dodecane-1,12-diyl,and the like.

The term “alkanecycloalkane” refers to a hydrocarbon group in which analkyl group is bonded to a cycloalkane group, wherein alkyl andcycloalkane are as defined herein. In certain embodiments, analkanecycloalkane group is C₇₋₂₀ alkanecycloalkane, C₇₋₁₂alkanecycloalkane, and in certain embodiments C₇₋₁₀ alkanecycloalkane.In certain embodiments an alkanecycloalkane is selected frommethylcyclohexane:

The term “alkanecycloalkanediyl” refers to a diradical hydrocarbon groupderived by the removal of two hydrogen atoms from a single carbon atomor by the removal of a single hydrogen atom from two carbon atoms from aparent alkanecycloalkane group. In certain embodiments analkanecycloalkanediyl is selected from 4-methylcyclohexane-diyl:

The term “alkoxy” refers to an alkyl-O— group where alkyl is as definedherein. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy,isopropoxy, and n-butoxy. In certain embodiments, an alkoxy group isC₁₋₈ alkoxy, C₁₋₆ alkoxy, C₁₋₄ alkoxy, and in certain embodiments C₁₋₃alkoxy.

The term “alkyl” refers to a monoradical of a saturated or unsaturated,branched, or straight-chain acyclic hydrocarbon group having, forexample, from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, from 1 to6 carbon atoms, from 1 to 4 carbon atoms, or from 1 to 3 carbon atoms.Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like. The term“alkyl” is specifically intended to include groups having any degree orlevel of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds.

The term “alkyne-reactive group” as used herein refers to a functionalgroup capable of reacting with an alkyne in the presence or absence of acatalyst to form a triazole. Example of a catalyst includes Copper(I).Examples of alkyne-reactive groups include an azide group. In certainembodiments, an alkyne-reactive group is selected from Formula (A¹e1),Formula (A¹e2), and Formula (A¹d3):

The term “amine-reactive group” as used herein refers to a functionalgroup capable of reacting with a primary amine group, a secondary aminegroup, a hydrazine group, or a substituted hydrazine group to form anamide bond, a urea bond, a thiourea bond, a sulfonamide bond, acarbamate bond, an imine, or a hydrazone. Examples of an amine-reactivegroup include an aldehyde group, a ketone group, an NHS-ester group, asubstituted phenylester group, an isocyanate group, an isothiocyanategroup, and an alkyl imidate group. In certain embodiments, anamine-reactive group is selected from Formula (A¹b1), Formula (A¹b2),Formula (A¹b3), and Formula (A¹b4):

wherein each R⁸ and R⁹ is independently selected from hydrogen, C₁₋₄alkyl, substituted C₁₋₄ alkyl, C₁₋₄ heteroalkyl, substituted C₁₋₄heteroalkyl, C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₆₋₁₀ heteroaryl, andsubstituted C₆₋₁₀ heteroaryl; and L² is a leaving group such as ahalogen, an N-hydroxysuccinimidyl, a substituted N-hydroxysuccinimidyl,a phenol-yl, a substituted phenol-yl, a hydroxybenzotriazolyl, asubstituted hydroxybenzotriazolyl, an imidazolyl, and a substitutedimidazolyl.

The term “amino acid side chain” includes the side chains of naturallyoccurring standard amino acids, side chains of naturally occurringnon-standard amino acids, and side chains of non-naturally occurringamino acid derivatives. In certain embodiments, amino acid side chainincludes naturally occurring standard amino acid side chains.

The term “anthracycline derivative” refers to a compound having thebasic structural scaffold:

and is effective in treating leukemias, lymphomas, and breast, uterine,ovarian, and/or lung cancers. Anthracycline derivatives interchelatewith DNA and RNA, inhibit the enzyme topoisomerase II, and generateDNA-damaging free oxygen radicals. Examples of anthracycline derivativesinclude berubicin, daunorubicin, doxorubicin, epirubicin, idarubicin,amrubicin, pirarubicin, zorubicin, mitoxantrone, banoxantrone, andsabarubicin.

The term “anthracenedione derivative” refers to a compound having thebasic structural scaffolds:

and is effective in treating metastatic breast cancer, acutelymphoblastic leukaemia, acute myeloid leukemia, non-Hodgkin's lymphoma,and/or multiple sclerosis. Anthracenedione derivatives interchelate withDNA and inhibit the enzyme topoisomerase II. Examples of anthracenedionederivatives include to ledoxantrone, mitoxantrone, nortopixantrone,pixantrone, piroxantrone, and topixantrone.

The term “antibiotic” refers to a compound that kills or slows thegrowth of bacteria, fungi, and/or other microorganisms. Examples ofantibiotics include amikacin, amphotericin B, arbekacin, astromicin,bacitracin, balofloxacin, bederocin, bekanamycin, besifloxacin,brodimoprim, ciprofloxacin, clinafloxacin, colistin, daptomycin,dibekacin, enoxacin, framycetin, garenoxacin, gatifloxacin,gemifloxacin, gentamicin, gentamicin, grepafloxacin, hamycin,hexetidine, hygromycin B, ibacitabine, iclaprim, isepamicin, kanamycin,lomefloxacin, lucimycin, lymecycline, mepartricin, moxifloxacin,natamycin, nemonoxacin, neomycin B, neomycin C, netilmicin, norfloxacin,nystatin, omadacycline, oritavancin, paromomycin, pazufloxacin,perimycin A, perimycin B, perimycin C, pipemidic acid, polymyxin B,puromycin, radezolid, retaspimycin, ribostamycin, rimocidin, sisomicin,sitafloxacin, sparfloxacin, spectinomycin, streptomycin, sulfacetamide,sulfadiazine, sulfadimethoxine, sulfadimidine, sulfafurazole, sulfalene,sulfamazone, sulfamerazine, sulfamethizole, sulfamethoxazole,sulfamethoxypyridazine, sulfametomidine, sulfametoxydiazine,sulfametrole, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole,sulfapyridine, sulfathiazole, sulfathiourea, sulfisomidine, teicoplanin,telavancin, tanespimycin, temafloxacin, tetroxoprim, tigecycline,tobramycin, tosufloxacin, trimethoprim, trimethoprim, trovafloxacin,tyrothricin, ulifloxacin, valnemulin, vancomycin, verdamicin, andzabofloxacin.

The term “antifolate” refers to a compound that is an analog of folicacid that inhibits the enzyme dihydrofolate reductase, thymidylatesynthase, and/or other enzyme associated with the metabolism ofnucleotides. Antifolates are known to be useful in treating cancer,rheumatoid arthritis, lupus, scleroderma, psoriasis, asthma,sarcoidosis, primary biliary cirrhosis, polymyositis, and/orinflammatory bowel disease. Examples of antifolates include aminopterin,folitixorin, methotrexate, pemetrexed, pralatrexate, raltitrexed,pelitrexol, pyrimethamine, talotrexin, and trimethoprim.

The term “arenediyl” refers to an aromatic hydrocarbon diradical derivedby the removal of two hydrogen atoms from a single carbon atom or by theremoval of a single hydrogen atom from two carbon atoms of a parentaromatic ring system. In certain embodiments, an arenediyl group isC₆₋₂₀ arenediyl, C₆₋₁₂ arenediyl, C₆₋₁₀ arenediyl, and in certainembodiments, C₆₋₈ arenediyl. Examples of arenediyl groups includebenzene-1,2-diyl, benzene-1,3-diyl, benzene-1,4-diyl,naphthalene-1,6-diyl, and the like.

The term “aryl” refers to a monovalent aromatic hydrocarbon radicalderived by the removal of one hydrogen atom from a single carbon atom ofa parent aromatic ring system. Aryl benzene; bicyclic ring systemswherein at least one ring is carbocyclic and aromatic, for example,naphthalene, indane, and tetralin; and tricyclic ring systems wherein atleast one ring is carbocyclic and aromatic, for example, fluorene. Arylencompasses multiple ring systems having at least one carbocyclicaromatic ring fused to at least one carbocyclic aromatic ring,cycloalkyl ring, or heterocycloalkyl ring. For example, aryl includes aphenyl ring fused to a 5- to 7-membered heterocycloalkyl ring containingone or more heteroatoms chosen from N, O, and S. For such fused,bicyclic ring systems wherein only one of the rings is a carbocyclicaromatic ring, the radical carbon atom may be at the carbocyclicaromatic ring or at the heterocycloalkyl ring. Examples of aryl groupsinclude, but are not limited to, groups derived from aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,hexylene, as-indacene, s-indacene, indane, indene, naphthalene,octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene,and the like. In certain embodiments, an aryl group can have from 6 to20 carbon atoms (C₆₋₂₀), from 6 to 12 carbon atoms (C₆₋₁₂), from 6 to 10carbon atoms (C₆₋₁₀), and in certain embodiments from 6 to 8 carbonatoms (C₆₋₈). Aryl, however, does not encompass or overlap in any waywith heteroaryl, separately defined herein.

The term “aurora kinase inhibitor” refers to a compound that inhibitsthe enzyme aurora kinase, which regulates cellular mitosis. Aurorakinase inhibitors are being investigated for the treatement of cancer.Examples of aurora kinase inhibitors include barasertib, hesperadin, andtozasertib.

The term “avidin-binding group” as used herein refers to a biotin, abiotin derivative such as desthiobiotin, iminobiotin, bisnorbiotin,tetranorbiotin, biotin sulfoxide, biotin sulfone, and iminobiotintrifluoroacetamide, or a Strep-tag (a synthetic peptide consisting of anN-terminal or C-terminal eight amino acid sequence:Trp-Ser-His-Pro-Gln-Phe-Glu-Lys) capable of binding to avidin,deglycosylated avidin, streptavidin, Strep-Tactin or related proteins.In certain embodiments, an avidin-binding group is selected from Formula(A¹c1), Formula (A¹c2), and Formula (A¹C3):

The term “azide-reactive group” as used herein refers to a functionalgroup capable of reacting with an azide in the presence or absence of acatalyst to form a triazole. Example of a catalyst includes Copper(I).Examples of azide-reactive groups include a terminal alkyne group and aninternal alkyne group. In certain embodiments, an azide-reactive groupis selected from Formula (A¹f1), Formula (A¹f2), Formula (A¹f3), Formula(A¹f4), and Formula (A¹f5):

The term “camptotheca derivative” refers to a compound having the basicstructural scaffold:

and is effective in treating colon, ovarian, and/or lung cancers.Camptotheca derivatives inhibit the enzyme topoisomerase I and interferewith the unwinding of DNA. Examples of camptotheca derivatives includebelotecan, atiratecan, exatecan, namitecan,7-nbutyl-10-amino-camptothecin, and7-n-butyl-9-amino-10,11-methylenedixoy-camptothecin.

The term “cathepsin K inhibitor” refers to a compound that inhibits theenzyme cathepsin K, which is associated with bone resorption. CathepsinK inhibitors are being investigated for the treatment of bone cancermetastases. Examples of cathepsin K inhibitors include dutacatib andodanacatib.

The term “colchicine derivative” refers to a compound having the basicstructural scaffold:

and is potentially effective in treating cancer. Colchicine derivativesbind to tubulin β subunit and inhibit microtubule assembly. Examples ofcolchicine derivatives include demecolcine.

The term “crosslinker” as used herein refers to any chemical agent thatjoins two or more molecules through covalent bond(s) or through stronghydrogen-bonding(s).

The term “cyclin-dependent kinase inhibitor” refers to a compound thatinhibits the enzyme cyclin-dependent kinase, which regulates cellularmitosis and transcription. Cyclin-dependent kinase inhibitors are beinginvestigated for the treatment of cancer. Examples of cyclin-dependentkinase inhibitors include dinaciclib and seliciclib.

The term “cycloalkane” refers to a saturated or partially saturatedcyclic or polycyclic hydrocarbon group. In certain embodiments, acycloalkane group is C₃₋₁₂ cycloalkane, C₃₋₈ cycloalkane, C₃₋₆cycloalkane, and in certain embodiments, C₅₋₆ cycloalkane.

The term “cycloalkanediyl” refers to a diradical cyclic or polycyclichydrocarbon group. In certain embodiments, a cycloalkane-diyl group isC₃₋₁₂ cycloalkane-diyl, C₃₋₈ cycloalkane-diyl, C₃₋₆ cycloalkanediyl, andin certain embodiments, C₅₋₆ cycloalkanediyl. Examples ofcycloalkanediyl groups include cyclohexane-1,4-diyl,cyclohexane-1,3-diyl, and cyclohexane-1,2-diyl.

The term “cycloalkyl” refers to a saturated or unsaturated cyclic orpolycyclic hydrocarbon monoradical group. In certain embodiments, acycloalkyl group is C₃₋₁₂ cycloalkyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl,and in certain embodiments, C₅₋₆ cycloalkyl.

The term “dipeptidyl peptidase IV inhibitor” refers to a compound thatinhibits the enzyme dipeptidyl peptidase IV, which is expressed on thesurface of most cell types and is associated with immune regulation,signal transduction and apoptosis. Examples of dipeptidyl peptidase IVinhibitors include talabostat.

The term “dolastatin derivative” refers to a compound that is isolatedor derived from the sea hare Dolabella auricularia or a structuralanalog thereof that binds to tubulin β subunit and inhibits microtubuleassembly. Dolastatin derivatives are potentially effective in treatingcancer. Examples of dolastatin derivatives include auristatin E,monomethyl auristatin E, auristatin F, monomethyl auristatin F,dolastatin 10, monomethyl dolastatin 10, dolastatin 12, dolastatin 15,soblidotin, monomethyl and dolastatin 16.

The term “duocarmycin derivative” refers to a compound that is isolatedor derived from Streptomyces sp. or a structural analog thereof thatalkylates DNA at minor groove sites. Duocarmycin derivatives arepotentially effective in treating cancer. Examples of duocarmycinderivatives include duocarmycin A, duocarmycin SA, duocarmycin B, andduocarmycin B1.

The term “ecteinascidin derivative” refers to a compound that isisolated or derived from the sea squirt Ecteinascidia turbinata or astructural analog thereof that produces superoxide, resulting in DNAcleavage. Ectienascidin derivatives are potentially effective intreating cancer. Examples of ecteinascidin derivatives includetrabectedin.

The term “enediyne derivative” refers to a compound that is isolated orderived from a bacterial natural product or a structural analog thereofcharacterized by either nine- and ten-membered rings containing twotriple bonds separated by a double bond. Enediyne derivatives bind toand cleave DNA and are potentially effective in treating cancer.Examples of enediyne derivatives include calicheamicin γ1, calicheamicinT, esperamicin A1, esperamicin C, esperamicin D, dynemicin A, dynemicinH, dynemicin M, dynemicin N, dynemicin O, dynemicin P, dynemicin Q,dynemicin S, neocarzinostatin chromophore, and uncialamycin.

The term “epothilone derivative” refers to a compound that is isolatedor derived from a myxobacterium Sorangium cellulosum or a structuralanalog thereof that interferes with mitotic spindle assembly. Epothilonederivatives are potentially effective in treating cancer, such as breastcancer. Examples of epothilone derivatives include ixabepilone and21-aminoepothilone B.

The term “halichondrin derivative” refers to a compound isolated orderived from the marine sponge Halichondria okadai or a structuralanalog thereof that interferes with formation of microtubules.Halichondrin derivatives are effective in treating breast cancer.Examples of halichondrin derivatives include eribulin.

The term “heat shock protein 90 (Hsp90) inhibitor” refers to a compoundthat binds to and interferes with Hsp90, which plays an important rolein oncogenesis. Examples of Hsp90 inhibitors include geldanamycin andalvespimycin.

The term “hemiasterlin derivative” refers to a compound that is isolatedor derived from marine sponges (Cymbastela sp., Hemiasterella minor,Siphonochalina sp., and Auletta sp.) or a structural analog thereof thatdepolymerizes microtubules and inteferes with cell division.Hemiasterlin derivatives are potentially effective in treating cancer.Examples of hemiasterlin derivatives include taltobulin and HTI-286.

The term “heteroalkanearenediyl” refers to an alkanenearenediyl group inwhich one or more of the carbon atoms are replaced with a heteroatom(e.g., N, O, S, P, or Si).

The term “heteroalkanecycloalkanediyl” refers to analkanecycloalkanediyl group in which one or more of the carbon atoms arereplaced with a heteroatom (e.g., N, O, S, P, or Si).

The term “heteroalkanediyl” refers to an alkanediyl group in which oneor more of the carbon atoms is replaced with a heteroatom (e.g., N, O,S, P, or Si).

The term “heteroalkyl” refers to an alkyl group in which one or more ofthe carbon atoms are replaced with a heteroatom (e.g., N, O, S, P, orSi).

The term “heteroarenediyl” refers to an arenediyl group wherein one ormore of the carbon atoms are replaced with a heteroatom (e.g., N, O, S,P, or Si). Examples of heteroarenediyl groups include furane-diyl andpyridine-diyl.

The term “heteroaryl” refers to an aryl group wherein one or more of thering carbon atoms are replaced with a heteroatom (e.g., N, O, S, P, orSi). Examples of heteroaryl groups include, but are not limited to,monoradicals of acridine, arsindole, carbazole, β-carboline, chromane,chromene, cinnoline, furan, imidazole, indazole, indole, indoline,indolizine, isobenzofuran, isochromene, isoindole, isoindoline,isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,oxazole, perimidine, phenanthridine, phenanthroline, phenazine,phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, and the like. In certain embodiments, a heteroarylgroup is C₅₋₂₀ heteroaryl, C₅₋₁₂ heteroaryl, C₅₋₈ heteroaryl, and incertain embodiments, C₅₋₆ heteroaryl. In certain embodiments heteroarylgroups are those derived from thiophene, pyrrole, benzothiophene,benzofuran, indole, pyridine, quinoline, imidazole, oxazole, andpyrazine.

The term “heterocycloalkanediyl” refers to a cycloalkanediyl group inwhich one or more of the carbon atoms are replaced with a heteroatom(e.g., N, O, S, P, or Si).

The term “heterocycloalkyl” refers to a cycloalkyl group in which one ormore of the carbon atoms are replaced with a heteroatom (e.g., N, O, S,P, or Si).

The term “histone deacetylase inhibitor” refers to a compound thatinterferes with the enzyme histone deacetylase, which involves with thecoiling of DNA around histones. Histone diacetylase inhibitors are beinginvestigated for the treatment of lymphoma, breast, and lung cancers.Examples of histone deacetylase inhibitors include entinostat,mocetinostat, panobinostat, and tacedinaline.

The term “immunomodulator” refers to a compound that stimulates and/orsuppresses the immune system. Examples of immunomodulators includeapilimod, balamapimod, dilmapimod, epetirimod, fingolimod, golotimod,imiquimod, lenalidomide, losmapimod, myriocin, pamapimod, resiquimod,gusperimus, pomalidomide, and sotirimod.

The term “kahalalide derivative” refers to a compound that is isolatedor derived from to the marine mollusk Elysia rufescens or a structuralanalog thereof that is active against certain human prostate and breastcancer cell lines. Kahalalide derivatives are potentially effective intreating cancer. Examples of kahalalide derivatives include kahalalide Fand elisidepsin.

The term “kinesin-related motor protein Eg5 inhibitor” refers to acompound that inhibits the motor protein Eg5, which is involved in theregulation of spindle formation during mitosis. Kinesin-related motorprotein Eg5 inhibitors are being investigated for the treatment ofcancer. Examples of kinesin-related motor protein Eg5 inhibitor includelitronesib.

The term “kinesin spindle protein inhibitor” refers to a compound thatinhibits the kinesin spindle protein, which involves in the assembly ofthe bipolar spindle during cell division. Kinesin spindle proteininhibitors are being investigated for the treatment of cancer. Examplesof kinesin spindle protein inhibitor include ispinesib.

The term “ligand” as used herein refers to an organic compound orinorganic substrate that contains or is functionalized to contain atleast one thiol group, at least one primary amine group, at least onesecondary amine group, at least one biotin-binding group, at least onephotoreactive group, at least one alkyne group, at least one azidegroup, or a combination of any of the foregoing. The function of theligand, for example, is to prolong the in-vivo half-life of the drug,reduce dosing frequency, lower toxicity, enhance the targeted deliveryof the drug, and/or enable parallel in-vitro analysis. The inorganicsubstrate may be, for example, a glass bead or surface and a gold beador surface, The organic compound may be, for example, a C₆₋₂₀hydrocarbon, a natural or modified peptide, a natural or modifiedprotein, a natural or modified antibody, a natural or modifiednucleoside, a natural or modified nucleotide, a natural or modifiedoligonucleotide, a sugar, a natural or modified oligosaccharide, anaminoglycoside (antibiotic), or a natural or modified polymer orcopolymer such as a polylactide, a polystyrene surface, a polystyrenebead, a dendrimer, a polyalkylene oxide, or a polyethylene oxide. Aligand can contain a thiol group, an amine group, a biotin-bindinggroup, an alkyne group, an azide group, and/or a photoreactive group, ormay be functionalized to contain thiol group, an amine group, abiotin-binding group, an alkyne group, an azide group, and/or aphotoreactive group.

Examples of peptides include glutathione, carnosine, and pantetheine.

Examples of proteins include bovine serum albumin, human serum albumin,avidin, and strepavidin.

Examples of antibodies include polyclonal antibodies, monoclonalantibodies, murine monoclonal antibodies, chimeric monoclonalantibodies, fusion proteins, humanized monoclonal antibodies, and humanmonoclonal antibodies. In certain embodiments, an antibody is ahumanized monoclonal antibody and is selected from Afutuzumab,Alemtuzumab, Bevacizumab, Bivatuzumab, Cantuzumab, Citatuzumab,Dacetuzumab, Elotuzumab, Etaracizumab, Farletuzumab, Gemtuzumabozogamicin, Inotuzumab ozogamicin, Labetuzumab, Lintuzumab, Matuzumab§,Milatuzumab, Nimotuzumab, Oportuzumab monatox, Pertuzumab, Sibrotuzumab,Tacatuzumab tetraxetan, Tigatuzumab, Trastuzumab, Tucotuzumabcelmoleukin, Veltuzumab, Aselizumab, Apolizumab, Benralizumab,Cedelizumab, Certolizumab, Daclizumab, Eculizumab, Efalizumab,Epratuzumab, Erlizumab, Fontolizumab, Mepolizumab, Natalizumab,Ocrelizumab, Omalizumab, Pascolizumab, Pexelizumab, PRO 140, Reslizumab,Rontalizumab, Rovelizumab, Ruplizumab, Siplizumab, Talizumab,Teplizumab, Tocilizumab, Toralizumab, Vedolizumab, Visilizumab, TGN1412,Ibalizumab, Tefibazumab, Alacizumab pegol, Bevacizumab/Ranibizumab,Etaracizumab, Tadocizumab, Bapineuzumab, Solanezumab, Tanezumab,Urtoxazumab, Felvizumab, Motavizumab, Palivizumab, Lebrikizumab, andRanibizumab. In certain embodiments, an antibody is a murine monoclonalantibody and is selected from Abagovomab, Igovomab, Oregovomab,Afelimomab, Elsilimomab, Faralimomab, Gavilimomab, Inolimomab,Maslimomab, Nerelimomab, Odulimomab, Telimomab aritox, Vepalimomab,Zolimomab aritox, Altumomab pentetate, Anatumomab mafenatox,Arcitumomab, Bectumomab, Blinatumomab, CC49, Detumomab, Ibritumomabtiuxetan, Minretumomab, Mitumomab, Naptumomab estafenatox, Nofetumomabmerpentan, Pemtumomab, Pintumomab, Satumomab pendetide, Taplitumomabpaptox, Tenatumomab, Tositumomab, 3F8, Besilesomab, Fanolesomab,Lemalesomab, Sulesomab, Biciromab, Imciromab, Capromab pendetide,Edobacomab, Edrecolomab, and Nacolomab tafenatox. In certainembodiments, an antibody is a chimeric monoclonal antibody and isselected from Bavituximab, Brentuximab vedotin, Cetuximab, Siltuximab,Rituximab, Abciximab, Volociximab, Basiliximab, Clenoliximab, Galiximab,Gomiliximab, Infliximab, Keliximab, Lumiliximab, Priliximab,Teneliximab, Vapaliximab, Ecromeximab, and Pagibaximab. In certainembodiments, an antibody is a human monoclonal antibody and is selectedfrom Adalimumab, Atorolimumab, Fresolimumab, Golimumab, Lerdelimumab,Metelimumab, Morolimumab, Ipilimumab, Tremelimumab, Bertilimumab,Zanolimumab, Briakinumab, Canakinumab, Ustekinumab, Adecatumumab,Belimumab, Cixutumumab, Conatumumab, Figitumumab, Iratumumab,Lexatumumab, Lucatumumab, Mapatumumab, Necitumumab, Ofatumumab,Olaratumab, Panitumumab, Pritumumab, Robatumumab, Votumumab,Zalutumumab, Denosumab, Stamulumab, Efungumab, Exbivirumab, Foravirumab,Libivirumab, Rafivirumab, Regavirumab, Sevirumab, Tuvirumab, Nebacumab,Panobacumab, Raxibacumab, Ramucirumab, Gantenerumab, and Glembatumumab.

Examples of nucleosides include thymidine, cytidine, uridine, adenosine,and guanosine.

Examples of oligonucleotides include single-stranded and double-strandedoligoribonucleotides, oligoribonucleotide derivatives,oligodeoxyribonucleotides, and oligodeoxyribonucleotide derivatives suchas phosphorothioates, phosphoramidates, and phosphorothioamidates.

Examples of oligonucleotides also include oblimersen and imetelstat.

Examples of sugars include glucosamine.

Examples of aminoglycosides include streptomycin, neomycin, framycetin,paromomycin, ribostamycin, kanamycin, amikacin, arbekacin, bekanamycin,dibekacin, tobramycin, spectinomycin, hygromycin B, paromomycin sulfate,gentamicin, netilmicin, sisomicin, isepamicin, verdamicin, andastromicin.

Examples of oligosaccharides include polyglucosamine (chitosan).

Examples of polymers include polyethylene glycol (PEG), monomethylpolyethylene glycol (MPEG), polypropylene glycol (PPG), polylactide,N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, andpoly(styrene-co-maleic acid). In certain embodiments, the polymer isMPEG having a number average molecular weight from about 200 to about60,000 Daltons, from about 1,000 to about 40,000 Daltons, and in certainembodiments, from about 2,000 to about 12,500 Daltons.

Examples of dendrimers include poly(amidoamine) dentrimers (PAMAM) andpoly(propylenimine) dentrimers (PPI).

The term “microtubule interference compounds” refers to a class ofcompounds that disrupt the polymerization or depolymerization ofmicrotubules during mitosis. Microtublue interference compounds arebeing used and investigated for the treatment of various cancers.Examples of microtubule interference compounds include vinca alkaloidderivatives, cevipabulin, denibulin, and ombrabulin.

The term “parent aromatic ring system” refers to an unsaturated cyclicor polycyclic ring system having a conjugated π electron system.Included within the definition of “parent aromatic ring system” arefused ring systems in which one or more of the rings are aromatic andone or more of the rings are saturated or unsaturated, such as,fluorene, indane, indene, phenalene, etc. Examples of parent aromaticring systems include, but are not limited to, aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,hexalene, as-indacene, s-indacene, indane, indene, naphthalene,octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,pleiadene, pyrene, pyranthrene, rubicene, triphenylene, andtrinaphthalene.

The term “parent heteroaromatic ring system” refers to a parent aromaticring system in which one or more carbon atoms (and any associatedhydrogen atoms) are independently replaced with the same or differentheteroatom. Examples of heteroatoms to replace the carbon atoms include,but are not limited to, N, P, O, S, Si, etc. Specifically includedwithin the definition of “parent heteroaromatic ring systems” are fusedring systems in which one or more of the rings are aromatic and one ormore of the rings are saturated or unsaturated, such as, arsindole,benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene,etc. Examples of parent heteroaromatic ring systems include, but are notlimited to, arsindole, carbazole, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, and xanthene.

The term “patient” includes mammals, such as for example, humans. Theterms “patient” and “patient” are used interchangeably.

The term “pharmaceutical composition” refers to at least one compoundand a pharmaceutically acceptable vehicle with which the compound isadministered to a patient.

The term “pharmaceutically acceptable” refers to approved or approvableby a regulatory agency of the Federal or a state government or listed inthe U.S. Pharmacopoeia or other generally recognized pharmacopoeia foruse in animals, including humans.

The term “pharmaceutically acceptable salt” refers to a salt of acompound, which possesses the desired pharmacological activity of theparent compound. Such salts include acid addition salts, formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like; or formed with organicacids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, lauryl sulfuric acid, gluconic acid, glutamic acid,hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, andthe like; and salts formed when an acidic proton present in the parentcompound is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth ion, or an aluminum ion; or coordinates with an organicbase such as ethanolamine, diethanolamine, triethanolamine,N-methylglucamine, and the like. In certain embodiments, apharmaceutically acceptable salt is the hydrochloride salt. In certainembodiments, a pharmaceutically acceptable salt is the sodium salt. Theterm “pharmaceutically acceptable salt” includes hydrates and othersolvates, as well as salts in crystalline or non-crystalline form.

The term “pharmaceutically acceptable vehicle” refers to apharmaceutically acceptable diluent, a pharmaceutically acceptableadjuvant, a pharmaceutically acceptable excipient, a pharmaceuticallyacceptable carrier, or a combination of any of the foregoing with whicha compound can be administered to a patient and which does not destroythe pharmacological activity thereof and which is nontoxic whenadministered in doses sufficient to provide a therapeutically effectiveamount of the compound.

The term “photoreactive group” as used herein refers to a functionalgroup capable of reacting with a primary, secondary or tertiary amineupon exposure to actinic radiation, such as ultraviolet light, to format least one covalent bond. Examples of photoreactive groups include anazide group, a diaziridine group, a coumarin group, and a psoralengroup. In certain embodiments, a photoreactive group is selected fromFormula (A¹d1), Formula (A¹d2), Formula (A¹d3), Formula (A¹d4), Formula(A¹d5), Formula (A¹d6), Formula (A¹d7), and Formula (A¹d8):

Examples of photoreactive groups are also disclosed in U.S. PublicationNo. 2001/00022761.

The term “poly (ADP-ribose) polymerase (PARP) inhibitor” refers to acompound that inhibits the enzyme PARP, which is associated with DNArepair and programmed cell death. Examples of a PARP inhibitors includeveliparib.

The term “purine analog” refers to a compound that mimics the nucleosideadenosine, nucleoside guanosine, nucleobase adenine, or nucleobaseguanine and interferes with the DNA replication. Purine analogs areeffective in treating certain cancers. Examples of purine analogsinclude deoxycoformycin, cladribine, clofarabine, fludarabine,thioguanine, and mercaptopurine.

The term “pyrimidine analog” refers to a compound that mimics thedeoxynucleoside thymidine, nucleoside cytidine, nucleoside uridine,nucleobase thymine, nucleobase cytosine or nucleobase uracil andinterferes with the DNA replication. Pyrimidine analogs are effective intreating certain cancers. Examples of pyrimidine analogs includeazacitidine, cytarabine, decitabine, and gemcitabine.

The term “pyrrolobenzodiazepine” refers to a compound that is isolatedor derived from Streptomyces sp. or a structural analog thereof thatalkylates DNA at minor groove sites. Pyrrolobenzodiazepine ispotentially effective in treating cancer. Examples ofpyrrolobenzodiazepine include abbeymycin, anthramycin, centanamycin,chicamycin, mazethramycin, porothramycin A, porothramycin B,sibanomycin, and sibiromycin.

The term “streptomyces” refers to a compound that is isolated or derivedfrom the bacteria Streptomyces or a structural analog thereof that hasantibacterial, antifungal, anti-parasitic, and/or antineoplasticproperties. Examples of streptomyces include actinomycin D,7-aminoactinomycin D, bleomycin, mitomycin, and staurosporine.

The term “substituted” refers to a group in which one or more hydrogenatoms are each independently replaced with the same or differentsubstituent(s). In certain embodiments, a substituent is selected fromhalogen, —S(O)₂OH, —S(O)₂—C₁₋₆ alkyl, —SH, —S—C₁₋₆ alkyl, —COOH, —CONH₂,—N₃, —NO₂, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —CN, ═O, C₁₋₆ alkyl,—CF₃, —OH, C₆₋₈ aryl, C₁₋₆ heteroalkyl, C₅₋₈ heteroaryl, C₁₋₆ alkoxy,C₁₋₆ acyl, and —COR where R is C₁₋₆ alkyl. In certain embodiments, asubstituent is chosen from —OH, —NH₂, and C₁₋₆ alkyl.

The term “therapeutic agent” or “drug” refers to a compound known to beor believed to be effective in treating a disease in a patient.

The term “therapeutically effective amount” refers to the amount of acompound that, when administered to a patient for treating a disease ina patient, is sufficient to reduce, minimize, and/or prevent thedisease. A “therapeutically effective amount” can vary depending, forexample, on the compound, the nature or cause of the disease, severityof the disease, the age, weight, and/or health of the patient to betreated, and the judgment of the prescribing physician. An appropriateamount in any given instance can be ascertained by those skilled in theart or capable of determination by routine experimentation. The terms“therapeutically effective amount” and “prophylactically effectiveamount” are used interchangeably. A therapeutically effective amount canalso mean a dose that has been recommended or approved by any of thevarious regulatory or advisory organizations in the medical orpharmaceutical arts (e.g., FDA, AMA) or by the manufacturer or supplier.

The term “therapeutically effective dose” refers to a dose that provideseffective treatment of a disease or disorder in a patient. Atherapeutically effective dose can vary from compound to compound, andfrom patient to patient, and can depend upon factors such as thecondition of the patient and the route of delivery. A therapeuticallyeffective dose can be determined in accordance with routinepharmacological procedures known to those skilled in the art.

The term “thiol-reactive group” as used herein refers to a functionalgroup capable of reacting with a thiol group to form a thiol ether bond,a disulfide bond, or a thiourea bond. Examples of a thiol-reactive groupinclude a vinyl group (—CH═CH₂), a haloalkyl group, a haloacetyl group,and an isocyanate group (—NCO). In certain embodiments a thiol-reactivegroup is selected from Formula (A¹a1), Formula (A¹a2), Formula (A¹a3),and Formula (A¹a4):

wherein each R⁸ and R⁹ is independently selected from hydrogen, C₁₋₄alkyl, substituted C₁₋₄ alkyl, C₁₋₄ heteroalkyl, substituted C₁₋₄heteroalkyl, C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₆₋₁₀ heteroaryl, andsubstituted C₆₋₁₀ heteroaryl; and each E is selected from F, Cl, Br, andI.

The term “topoisomerase inhibitor” refers to a compound that inhibitsthe enzyme topoisomerase, which involves in the unwinding and winding ofDNA during transcription and replication. Topoisomerase inhibitors arebeing used and investigated for the treatment of various cancers.Examples of topoisomerase inhibitors include camptotheca derivatives andedotecarin.

The term “treating” or “treatment” of any disease or disorder refers toarresting or ameliorating a disease, disorder, or at least one of theclinical symptoms of a disease or disorder, reducing the risk ofacquiring a disease, disorder, or at least one of the clinical symptomsof a disease or disorder, reducing the development of a disease,disorder or at least one of the clinical symptoms of the disease ordisorder, or reducing the risk of developing a disease or disorder or atleast one of the clinical symptoms of a disease or disorder. “Treating”or “treatment” also refers to inhibiting the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both,and to inhibiting at least one physical parameter which may or may notbe discernible to the patient. In certain embodiments, “treating” or“treatment” refers to delaying the onset of the disease or disorder orat least one or more symptoms thereof in a patient which may be exposedto or predisposed to a disease or disorder even though that patient doesnot yet experience or display symptoms of the disease or disorder.

The term “tubulysin derivative” refers to a compound having the basicstructural scaffold:

and is potentially effective in treating cancer. Tubulysin derivativesdepolymerize microtubules and induce mitotic arrest. Examples oftubulysin derivatives include tubulysin A, tubulysin B, and tubulysin D.

The term “tyrosine kinase inhibitor” refers to a compound that inhibitsthe enzyme tyrosine kinase, which regulates cellular activity throughthe phosphorylation of the amino acid tyrosine of a signaling protein.Tyrosine kinase inhibitors are effective in treating chronic myelogenousleukemia and are being for the treatment of other cancers. Examples oftyrosine kinase inhibitors include afatinib, bosutinib, canertinib,crizotinib, dacomitinib, dasatinib, dovitinib, erlotinib, fostamatinib,gefitinib, imatinib, intedanib, lapatinib, linifanib, masitinib,motesanib, neratinib, nilotinib, pazopanib, saracatinib, selumetinib,telatinib, tipifarnib, vandetanib, and vatalanib.

The term “vinca alkaloid derivative” refers to a compound isolated orderived from a plant Madagascar Periwinkle or a structural analogthereof that inhibits microtubule polymerization. Examples of vincaalkaloid derivatives include desacetylvinblastine hydrazide,vinblastine, vincristine, vindesine, vinflunine, and vinorelbine.

Compounds are named using Symyx Draw 3.3, Symyx Solutions Inc., 2010.

Reference is now made in detail to certain embodiments of compounds,compositions, and methods. The disclosed embodiments are not intended tobe limiting of the claims. To the contrary, the claims are intended tocover all alternatives, modifications, and equivalents.

Cleavable Conjugates

In certain embodiments, a compound provided by the present disclosurehas the structure of Formula (II):

or a salt thereof, wherein:

each A¹ is independently selected from a thiol-reactive group, anamine-reactive group, an avidin-binding group, a photoreactive group, analkyne-reactive group, and an azide-reactive group;

each X¹ and X³ is independently selected from a covalent bond, C₁₋₂₀alkanediyl, substituted C₁₋₂₀ alkanediyl, C₁₋₂₀ heteroalkanediyl,substituted C₁₋₂₀ heteroalkanediyl, C₃₋₁₂ cycloalkanediyl, substitutedC₃₋₁₂ cycloalkanediyl, C₃₋₁₂ heterocycloalkanediyl, substituted C₃₋₁₂heterocycloalkanediyl, C₄₋₂₀ alkanecycloalkanediyl, substituted C₄₋₂₀alkanecycloalkanediyl, C₄₋₂₀ heteroalkanecycloalkanediyl, substitutedC₄₋₂₀ heteroalkanecycloalkanediyl, C₆₋₂₀ arenediyl, substituted C₆₋₂₀arenediyl, C₆₋₂₀ heteroarenediyl, substituted C₆₋₂₀ heteroarenediyl,C₇₋₂₀ alkanearenediyl, substituted C₇₋₂₀ alkanearenediyl, C₆₋₂₀heteroalkanearenediyl, substituted C₆₋₂₀ heteroalkanearenediyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein:

-   -   each n1 and n3 is independently an integer selected from 0 to 5;        and    -   each n2 is independently an integer selected from 1 to 25;

each X² is independently selected from a covalent bond, —O—, —S—, —N—,—N═, —N═N—, —N═C—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—, —C(O)N—,—C(O)S—, —C(O)N—N═, —OP(O)(OH)O—, —OC(O)O—, —OC(O)N—, —NC(O)N—, and—NC(S)N;

each R¹ and R² is independently selected from hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆ heteroalkyl,C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₆₋₁₀ heteroaryl, and substitutedC₆₋₁₀ heteroaryl;

D is selected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and

n5 is an integer selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is thesame, and in certain embodiments, at least some A¹ are different.

In certain embodiments of a compound of Formula (II), each X¹ is thesame, and in certain embodiments, at least some X¹ are different.

In certain embodiments of a compound of Formula (II), each X² is thesame, and in certain embodiments, at least some X² are different.

In certain embodiments of a compound of Formula (II), each X³ is thesame, and in certain embodiments, at least some X³ are different.

In certain embodiments of a compound of Formula (II), each R¹ is thesame, and in certain embodiments, at least some R¹ are different.

In certain embodiments of a compound of Formula (II), each R² is thesame, and in certain embodiments, at least some R² are different.

In certain embodiments of a compound of Formula (II), each group withinthe brackets is the same, and in certain embodiments, at least one groupwithin the brackets is different.

In certain embodiments of a compound of Formula (II), each A¹ isindependently a moiety selected from Formula (A¹a1), Formula (A¹a2),Formula (A¹a3), Formula (A¹b1), Formula (A¹b2), Formula (A¹c1), Formula(A¹c2), Formula (A¹c3), Formula (A¹d1), Formula (A¹d2), Formula (A¹d3),Formula (A¹e1), Formula (A¹f1), and Formula (A¹f2):

wherein:

-   -   each R⁸ and R⁹ is independently selected from hydrogen, C₁₋₄        alkyl, substituted C₁₋₄ alkyl, C₁₋₄ heteroalkyl, substituted        C₁₋₄ heteroalkyl, C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₆₋₁₀        heteroaryl, and substituted C₆₋₁₀ heteroaryl;    -   each E is selected from F, Cl, Br, and I; and    -   each L² is selected from halogen, N-hydroxysuccinimidyl,        substituted N-hydroxysuccinimidyl, phenol-yl, substituted        phenol-yl, hydroxybenzotriazolyl, substituted        hydroxybenzotriazolyl, imidazolyl, and substituted imidazolyl.

In certain embodiments of a compound of Formula (II), each A¹ isindependently selected from a thiol-reactive group, each A¹ isindependently selected from an amine-reactive group, each A¹ isindependently selected from an avidin-binding group, and in certainembodiments, each A¹ is independently selected from a photoreactivegroup, each A¹ is independently selected from an alkyne-reactive group,and each A¹ is independently selected from an azide-reactive group.

In certain embodiments of a compound of Formula (II), each A¹ is athiol-reactive group and is independently selected from Formula (A¹a1),Formula (A¹a2), and Formula (A¹a3). In certain embodiments of a compoundof Formula (II), each A¹ is an amine-reactive group and is independentlyselected from Formula (A¹b1) and Formula (A¹b2). In certain embodimentsof Formula (II), each A¹ is an avidin-binding group and is independentlyselected from Formula (A¹c1), Formula (A¹c2), and Formula (A¹c3). Incertain embodiments of a compound of Formula (II), each A¹ is aphotoreactive group and is independently selected from Formula (A¹d1),Formula (A¹d2), and Formula (A¹d3). In certain embodiments of a compoundof Formula (II), each A¹ is an alkyne-reactive group of Formula (A¹e1).In certain embodiments of a compound of Formula (II), each A¹ is anazide-reactive group and is independently selected from Formula (A¹f1)and Formula (A¹f2).

In certain embodiments of a compound of Formula (II), each A¹ is Formula(A¹a1). In certain embodiments of a compound of Formula (II), each A¹ isFormula (A¹a1), wherein each R⁸ and R⁹ is independently selected fromhydrogen, C₁₋₄ alkyl and C₆₋₈ aryl; in certain embodiments, each R⁸ andR⁹ is independently selected from hydrogen, C₁₋₂ alkyl, and C₆ aryl; andin certain embodiments, each R⁸ and R⁹ is hydrogen.

In certain embodiments of a compound of Formula (II), each A¹ is Formula(A¹a2). In certain embodiments of a compound of Formula (II), each A¹ isFormula (A¹a2), wherein each R⁸ is selected from hydrogen and C₁₋₄alkyl; and in certain embodiments, each R⁸ is selected from hydrogen andmethyl.

In certain embodiments of a compound of Formula (II), each A¹ is Formula(A¹a3). In certain embodiments of a compound of Formula (II), each A¹ isFormula (A¹a3), wherein each E is selected from F, Cl, Br, and I; and incertain embodiments each E is selected from Br and I.

In certain embodiments of a compound of Formula (II), each A¹ is Formula(A¹b1). In certain embodiments of a compound of Formula (II) whereineach A¹ is Formula (A¹b1), each L² is selected from Cl,N-hydroxysuccinimidyl, sulfo-N hydroxysuccinimidyl, 4-nitrophenol-yl,pentafluorophenol-yl, 4-methyl sulfonylphenol-yl, andtrichlorophenol-yl.

In certain embodiments of a compound of Formula (II), each A¹ is Formula(A¹b2). In certain embodiments of a compound of Formula (II) whereineach A¹ is Formula (A¹b2), each R⁸ and R⁹ is independently selected fromhydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl, and each L² is selected from Cl,N-hydroxysuccinimidyl, sulfo-N hydroxysuccinimidyl, 4-nitrophenol-yl,pentafluorophenol-yl, 4-methyl sulfonylphenol-yl, andtrichlorophenol-yl. In certain embodiments of a compound of Formula (II)wherein each A¹ is Formula (A¹b2), each R⁸ and R⁹ is independentlyselected from hydrogen, methyl, ethyl, propyl, isopropyl, and phenyl,and each L² is selected from Cl, N-hydroxysuccinimidyl, sulfo-Nhydroxysuccinimidyl, 4-nitrophenol-yl, pentafluorophenol-yl, 4-methylsulfonylphenol-yl, and trichlorophenol-yl. In certain embodiments of acompound of Formula (II) wherein each A¹ is Formula (A¹b2), each R⁸ andR⁹ is hydrogen, and each L² is selected from Cl, N-hydroxysuccinimidyl,sulfo-N hydroxysuccinimidyl, 4-nitrophenol-yl, pentafluorophenol-yl,4-methyl sulfonylphenol-yl, and trichlorophenol-yl.

In certain embodiments of a compound of Formula (II), each A¹ is Formula(A¹c1). In certain embodiments of a compound of Formula (II), each A¹ isFormula (A¹c2). In certain embodiments of a compound of Formula (II),each A¹ is Formula (A¹c3). In certain embodiments of a compound ofFormula (II), each A¹ is Formula (A¹d1). In certain embodiments of acompound of Formula (II), each A¹ is Formula (A¹d2). In certainembodiments of a compound of Formula (II), each A¹ is Formula (A¹d3). Incertain embodiments of a compound of Formula (II), each A¹ is Formula(A¹e1). In certain embodiments of a compound of Formula (II), each A¹ isFormula (A¹f1). In certain embodiments of a compound of Formula (II),each A¹ is Formula (A¹f2).

In certain embodiments of a compound of Formula (II), each X¹ and X³ isindependently selected from a covalent bond, C₁₋₂₀ alkanediyl,substituted C₁₋₂₀ alkanediyl, C₃₋₁₂ cycloalkanediyl, substituted C₃₋₁₂cycloalkanediyl, substituted C₃₋₁₂ heterocycloalkanediyl, C₆₋₂₀arenediyl, substituted C₆₋₂₀ arenediyl, C₇₋₂₀ alkanearenediyl,substituted C₇₋₂₀ alkanearenediyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5 and each n2 isindependently an integer selected from 1 to 25.

In certain embodiments of a compound of Formula (II), each X¹ and X³ isindependently selected from a covalent bond, C₁₋₁₆ alkanediyl,substituted C₁₋₁₆ alkanediyl, C₃₋₆ cycloalkanediyl, benzene-diyl,substituted benzene-diyl, C₇₋₉ benzenealkane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5 and each n2 isindependently an integer selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each X¹ and X³ isindependently selected from a covalent bond, C₁₋₈ alkanediyl,substituted C₁₋₈ alkanediyl, C₃₋₈ cycloalkanediyl, benzene-diyl,substituted benzene-diyl, C₇₋₉ benzenealkane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂), wherein each n1 and n3 isindependently an integer selected from 0 to 3 and each n2 isindependently an integer selected from 1 to 10.

In certain embodiments of a compound of Formula (II), each X¹ isselected from C₁₋₂₀ alkanediyl, C₁₋₂₀ cycloalkanediyl, C₆₋₁₀ arenediyl,and C₇₋₂₀ alkanearenediyl. In certain embodiments of a compound ofFormula (II), each X³ is selected from C₁₋₂₀ alkanediyl, C₁₋₂₀cycloalkanediyl, C₆₋₁₀ arenediyl, and C₇₋₂₀ alkanearenediyl.

In certain embodiments of a compound of Formula (II), each X¹ is acovalent bond.

In certain embodiments of a compound of Formula (II), each X³ is acovalent bond.

In certain embodiments of a compound of Formula (II), each X¹ and X³ isindependently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3 and each n2 isindependently an integer selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each X¹ and X³ isindependently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, pentane-1,5-diyl,4-methylcyclohexane-diyl, benzene-1,2-diyl, benzene-1,3-diyl, andbenzene-1,4-diyl.

In certain embodiments of a compound of Formula (II), each X¹ is acovalent bond; and each X³ is selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, pentane-1,5-diyl,4-methylcyclohexane-diyl, benzene-1,2-diyl, benzene-1,3-diyl, andbenzene-1,4-diyl.

In certain embodiments of a compound of Formula (II), each X¹ isethane-1,2-diyl; and each X³ is selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, pentane-1,5-diyl,4-methylcyclohexane-diyl, benzene-1,2-diyl, benzene-1,3-diyl, andbenzene-1,4-diyl.

In certain embodiments of a compound of Formula (II), each X¹ ispentane-1,5-diyl; and each X³ is selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, pentane-1,5-diyl,4-methylcyclohexane-diyl, benzene-1,2-diyl, benzene-1,3-diyl, andbenzene-1,4-diyl.

In certain embodiments of a compound of Formula (II), each X¹ is4-methylcyclohexane-diyl; and X³ is selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, pentane-1,5-diyl,4-methylcyclohexane-diyl, benzene-1,2-diyl, benzene-1,3-diyl, andbenzene-1,4-diyl.

In certain embodiments of a compound of Formula (II) wherein each X¹and/or X³ is —(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, each n1 and n3 isindependently an integer selected from 0 to 5, an integer selected from0 to 4, an integer selected from 0 to 3, and in certain embodiments, aninteger selected from 0 to 2. In certain embodiments of a compound ofFormula (II) wherein each X¹ and/or X³ is—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, each n2 is independently aninteger selected from 1 to 25, an integer selected from 1 to 20, aninteger selected from 1 to 15, an integer selected from 1 to 10, aninteger selected from 1 to 5, an integer selected from 1 to 4, and incertain embodiments, an integer selected from 1 to 3.

In certain embodiments of a compound of Formula (II), each n1 and n3 isindependently an integer selected from 0 to 5, in certain embodiments,an integer selected from 0 to 4, and in certain embodiments, an integerselected from 0 to 3; and each n2 is independently an integer selectedfrom 1 to 25, in certain embodiments an integer selected from 1 to 20,in certain embodiments an integer selected from 1 to 15, in certainembodiments an integer selected from 1 to 10, and in certain embodimentsan integer selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each X² isselected from a covalent bond, —O—, —S—, —N—, —N═, —N═N—, —N═C—, —SO—,—SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—, —C(O)N—, —C(O)S—, —C(O)N—N═,—OP(O)(OH)O—, —OC(O)O—, —OC(O)N—, —NC(O)N—, and —NC(S)N. In certainembodiments of a compound of Formula (II), each X² is selected from acovalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—. In certain embodiments of acompound of Formula (II), each X² is selected from a covalent bond,—SO₂—, —SO₂N—, and —C(O)N—.

In certain embodiments of a compound of Formula (II), each R¹ and R² isindependently selected from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆ heteroalkyl, C₆₋₁₀ aryl,substituted C₆₋₁₀ aryl, C₆₋₁₀ heteroaryl, and substituted C₆₋₁₀heteroaryl.

In certain embodiments of a compound of Formula (II), each R¹ and R² isindependently selected from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆alkyl, and C₆₋₁₀ aryl. In certain embodiments of a compound of Formula(II), R¹ and R² are independently selected from hydrogen, methyl, ethyl,propyl, isopropyl, and phenyl. In certain embodiments of a compound ofFormula (II), each R¹ and R² is independently selected from hydrogen andmethyl. In certain embodiments of a compound of Formula (II), each R¹and R² is independently selected from hydrogen and ethyl. In certainembodiments of a compound of Formula (II), each R¹ and R² isindependently selected from hydrogen and propyl. In certain embodimentsof a compound of Formula (II), each R¹ and R² is independently selectedfrom hydrogen and isopropyl. In certain embodiments of a compound ofFormula (II), each R¹ and R² is independently selected from hydrogen andphenyl.

In certain embodiments of a compound of Formula (II), each R¹ and R² ishydrogen. In certain embodiments of a compound of Formula (II), each R¹is hydrogen and each R² is methyl. In certain embodiments of a compoundof Formula (II), each R¹ is hydrogen and each R² is ethyl. In certainembodiments of a compound of Formula (II), each R¹ is hydrogen and eachR² is propyl. In certain embodiments of a compound of Formula (II), eachR¹ is hydrogen and each R² is isopropyl. In certain embodiments of acompound of Formula (II), each R¹ is hydrogen and each R² is phenyl.

In certain embodiments of a compound of Formula (II), D is selected froma therapeutic agent having at least one primary amine group, atherapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group.

In certain embodiments of a compound of Formula (II), D is selected froma folic acid analog, a purine analog, a pyrimidine analog, ananthracycline derivative, a dolastatin derivative, a camptothecaderivative, an ectainascidin derivative, a colchicine derivative, aduocarmycin derivative, an enediyne derivative, an epothilonederivative, a halichondrin derivative, a kahalalide derivative, astreptomyces, a tubulysin derivative, a vinca alkaloid, an antifolate, ahemiasterlin, a cathepsin K inhibitor, dipeptidyl peptidase IVinhibitor, heat shock protein 90 (Hsp90) inhibitor, a histonedeacetylase inhibitor, an immunomodulator, an aurora kinase inhibitor, acyclin-dependent kinase inhibitor, tyrosine kinase inhibitor,kinesin-related motor protein Eg5 inhibitor, kinesin spindle proteininhibitor, microtubule interference compounds, topoisomerase inhibitor,and an antibiotic.

In certain embodiments of a compound of Formula (II), D is selected fromaminopterin, folitixorin, methotrexate, pemetrexed, pralatrexate,raltitrexed, pelitrexol, talotrexin, deoxycoformycin, cladribine,clofarabine, fludarabine, thioguanine, mercaptopurine, berubicin,daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin,pirarubicin, zorubicin, mitoxantrone, banoxantrone, ledoxantrone,nortopixantrone, pixantrone, piroxantrone, sabarubicin, topixantrone,monomethyl auristatin E, monomethyl auristatin F, monomethyl dolastatin10, dolastatin 15, belotecan, atiratecan, camptothecin, exatecan,irinotecan, namitecan, rubitecan, topotecan, demecolcine, duocarmycin A,duocarmycin SA, duocarmycin B, duocarmycin B1, abbeymycin, anthramycin,centanamycin, chicamycin, mazethramycin, porothramycin A, porothramycinB, sibanomycin, sibiromycin, trabectedin, calicheamicin γ1,calicheamicin T, esperamicin A1, esperamicin C, esperamicin D, dynemicinA, dynemicin H, dynemicin M, dynemicin N, dynemicin O, dynemicin P,dynemicin Q, dynemicin S, neocarzinostatin chromophore, uncialamycin,21-aminoepothilone B, eribulin, hemiasterlin, HTI-286, kahalatide F,elsamitrucin, lucanthone, melphalan, mitoguazone, nimustine,procarbazine, dacarbazine, amsacrine, 5-amino-4-oxo-pentanoic acid,methyl 5-amino-4-oxo-pentanoate, actinomycin D, 7-aminoactinomycin D,bleomycin, mitomycin, staurosporine, desacetylvinblastine hydrazide,vinblastine, vincristine, vindesine, vinflunine, vinorelbine, afatinib,apilimod, balamapimod, barasertib, bosutinib, canertinib, cevipabulin,crizotinib, dacomitinib, dasatinib, denibulin, dilmapimod, dinaciclib,dovitinib, dutacatib, duvoglustat, edotecarin, elisidepsin, entinostat,epetirimod, erlotinib, fingolimod, fostamatinib, gefitinib, golotimod,gusperimus, imatinib, imiquimod, intedanib, ispinesib, lapatinib,lenalidomide, linifanib, litronesib, losmapimod, metesind, mocetinostat,motesanib, masitinib, myriocin, neratinib, nilotinib, odanacatib,ombrabulin, pamapimod, panobinostat, pazopanib, plerixafor,pomalidomide, razupenem, resiquimod, sabarubicin, saracatinib,seliciclib, selumetinib, sotirimod, squalamine, tacedinaline,talabostat, taltobulin, telatinib, tipifarnib, tozasertib, vandetanib,vatalanib, veliparib, voreloxin, alvespimycin, amikacin, amphotericin B,arbekacin, astromicin, bacitracin, balofloxacin, bederocin, bekanamycin,besifloxacin, brodimoprim, ciprofloxacin, clinafloxacin, colistin,daptomycin, dibekacin, enoxacin, framycetin, garenoxacin, gatifloxacin,gemifloxacin, gentamicin, gentamicin, grepafloxacin, hamycin,hexetidine, hygromycin B, ibacitabine, iclaprim, isepamicin,kanamycin,lomefloxacin, lucimycin, lymecycline, mepartricin, moxifloxacin,natamycin, nemonoxacin, neomycin B, neomycin C, netilmicin, norfloxacin,nystatin, omadacycline, oritavancin, paromomycin, pazufloxacin,perimycin A, perimycin B, perimycin C, pipemidic acid, polymyxin B,puromycin, radezolid, retaspimycin, ribostamycin, rimocidin, sisomicin,sitafloxacin, sparfloxacin, spectinomycin, streptomycin, sulfacetamide,sulfadiazine, sulfadimethoxine, sulfadimidine, sulfafurazole, sulfalene,sulfamazone, sulfamerazine, sulfamethizole, sulfamethoxazole,sulfamethoxypyridazine, sulfametomidine, sulfametoxydiazine,sulfametrole, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole,sulfapyridine, sulfathiazole, sulfathiourea, sulfisomidine, teicoplanin,telavancin, tanespimycin, temafloxacin, tetroxoprim, tigecycline,tobramycin, tosufloxacin, trimethoprim, trimethoprim, trovafloxacin,tyrothricin, ulifloxacin, valnemulin, vancomycin, verdamicin, andzabofloxacin.

In certain embodiments of a compound of Formula (II), n5 is an integerselected from 1 to 20, from 1 to 5, and in certain embodiments, n5 is aninteger selected from 1 to 3. In certain embodiments, n5 is 1, n5 is 2,n5 is 3, and in certain embodiments, n5 is 4. In certain embodiments ofa compound of Formula (II), n5 is selected from 1, 2, 3, and 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a1), wherein each R⁸ and R⁹ is independentlyselected from hydrogen, C₁₋₄ alkyl, and C₆₋₁₀ aryl; each X¹ and X³ isindependently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is independentlyselected from a covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—,—C(O)—, —C(O)O—, —C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ andR² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; Dis selected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a1), wherein each R⁸ and R⁹ is independentlyselected from hydrogen and methyl; each X¹ and X³ is independentlyselected from a covalent bond, methane-diyl, ethane-1,2-diyl,propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl,heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl,undecane-1,11-diyl, dodecane-1,12-diyl, hexadecane-1,16-diyl,benzene-diyl, methylbenzene-diyl, propylbenzene-diyl,methylcyclohexane-diyl, and —(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—,wherein each n1 and n3 is independently an integer selected from 0 to 3,and each n2 is independently an integer selected from 1 to 20; each X²is selected from a covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—,and —C(O)N—; each R¹ and R² is independently selected from hydrogen,C₁₋₄ alkyl, and C₆₋₈ aryl; D is selected from a therapeutic agent havingat least one primary amine group and a therapeutic agent having at leastone secondary amine group; and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ ispentane-1,5-diyl; each X² is a covalent bond; each X³ is a covalentbond; each R¹ and R² is hydrogen; D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ isbenzene-1,3-diyl; each X² is a covalent bond; each X³ is a covalentbond; each R¹ and R² is hydrogen; D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ is4-methylcyclohexane-diyl; each X² is a covalent bond; each X³ is acovalent bond; each R¹ and R² is hydrogen; D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n5 isselected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ ispentane-1,5-diyl; each X² is a covalent bond; each X³ is a covalentbond; each R¹ is hydrogen; each R² is methyl; D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n5 isselected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ ispentane-1,5-diyl; each X² is a covalent bond; each X³ is a covalentbond; each R¹ and R² is hydrogen; D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ isbenzene-1,4-diyl; each X² is a covalent bond; each X³ ispropane-1,3-diyl; each R¹ and R² is hydrogen; D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n5 isselected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ is—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein n1 is 0, n2 is 2, andn3 is 2; each X² is a covalent bond; each X³ is a covalent bond; each R¹and R² is hydrogen; D is selected from a therapeutic agent having atleast one primary amine group and a therapeutic agent having at leastone secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ ispentane-1,5-diyl; each X² is —C(O)N—; each X³ is pentane-1,5-diyl; eachR¹ is hydrogen; each R² is methyl; D is selected from a therapeuticagent having at least one primary amine group and a therapeutic agenthaving at least one secondary amine group; and n5 is selected from 1 to4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ is4-methylcyclohexane-diyl; each X² is —C(O)N—; each X³ ispentane-1,5-diyl; each R¹ is hydrogen; each R² is methyl; D is selectedfrom a therapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n5 isselected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a2), wherein each R⁸ is selected from hydrogen,C₁₋₄ alkyl, and C₆₋₁₀ aryl; each X¹ and X³ is independently selectedfrom a covalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methyl cyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is selected froma covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ and R² isindependently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; D isselected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a2), each wherein R⁸ is selected from hydrogen andmethyl; each X¹ and X³ is independently selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈aryl; D is selected from a therapeutic agent having at least one primaryamine group and a therapeutic agent having at least one secondary aminegroup; and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a2), wherein each R⁸ is hydrogen; each X¹ is acovalent bond; each X² is a covalent bond; each X³ is a covalent bond;each R¹ and R² is hydrogen; D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a2), wherein each R⁸ is methyl; each X¹ is acovalent bond; each X² is a covalent bond; each X³ is a covalent bond;each R¹ and R² is hydrogen; D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a2), wherein each R⁸ is hydrogen; each X¹ is acovalent bond; each X² is —SO₂—; each X³ is methane-diyl; each R¹ and R²is hydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a2), wherein each R⁸ is hydrogen; each X¹ is acovalent bond; each X² is —SO₂—; each X³ is ethane-1,2-diyl; each R¹ andR² is hydrogen; D is selected from a therapeutic agent having at leastone primary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a2), wherein each R⁸ is hydrogen; each X¹ is acovalent bond; each X² is —SO₂N—; each X³ is pentane-1,5-diyl; each R¹and R² is hydrogen; D is selected from a therapeutic agent having atleast one primary amine group and a therapeutic agent having at leastone secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a2), wherein each R⁸ is methyl; each X¹ is acovalent bond; each X² is —C(O)N—; each X³ is pentane-1,5-diyl; each R¹and R² is hydrogen; D is selected from a therapeutic agent having atleast one primary amine group and a therapeutic agent having at leastone secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a2), wherein each R⁸ is methyl; each X¹ is acovalent bond; each X² is —C(O)N—; each X³ is 4-methylcyclohexane-diyl;each R¹ and R² is hydrogen; D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a2), wherein each R⁸ is methyl; each X¹ is acovalent bond; each X² is —C(O)N—; each X³ is pentane-1,5-diyl; each R¹is hydrogen; each R² is methyl; D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a2), wherein each R⁸ is methyl; each X¹ is acovalent bond; each X² is —C(O)N—; each X³ is 4-methylcyclohexane-diyl;each R¹ is hydrogen; each R² is methyl; D is selected from a therapeuticagent having at least one primary amine group and a therapeutic agenthaving at least one secondary amine group; and n5 is selected from 1 to4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a2), wherein each R⁸ is methyl; each X¹ is acovalent bond; each X² is —C(O)O—; each X³ is pentane-1,5-diyl; each R¹and R² is hydrogen; D is selected from a therapeutic agent having atleast one primary amine group and a therapeutic agent having at leastone secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹a3), wherein each E is selected from F, Cl, Br, and I; eachX¹ and X³ is independently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is selected froma covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ and R² isindependently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; D isselected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹a3), wherein each E is selected from F, Cl, Br, and I; eachX¹ and X³ is independently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈aryl; D is selected from a therapeutic agent having at least one primaryamine group and a therapeutic agent having at least one secondary aminegroup; and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a3), wherein each E is Br; each X¹ is a covalentbond; each X² is a covalent bond; each X³ is a covalent bond; each R¹ ishydrogen; each R² is methyl; D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a3), wherein each E is Br; each X¹ is a covalentbond; each X² is —C(O)N—; each X³ is pentane-1,5-diyl; each R¹ ishydrogen; each R² is methyl; D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a3), wherein each E is Br; each X¹ is a covalentbond; each X² is —C(O)N—; each X³ is 4-methylcyclohexane-diyl; each R¹is hydrogen; each R² is methyl; D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹a3), wherein each E is Br; each X¹ is a covalentbond; each X² is —C(O)O—; each X³ is pentane-1,5-diyl; each R¹ ishydrogen; each R² is methyl; D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹b1), wherein each L² is selected from halogen,N-hydroxysuccinimidyl, substituted N-hydroxysuccinimidyl, phenol-yl, andsubstituted phenol-yl; each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is selected froma covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ and R² isindependently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; D isselected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹b1), wherein each L² is selected from halogen,N-hydroxysuccinimidyl, substituted N-hydroxysuccinimidyl, phenol-yl, andsubstituted phenol-yl; each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈aryl; D is selected from a therapeutic agent having at least one primaryamine group and a therapeutic agent having at least one secondary aminegroup; and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹b1), wherein each L² is N-hydroxysuccinimidyl; eachX¹ is ethane-1,2-diyl; each X² is a covalent bond; each X³ is a covalentbond; each R¹ and R² is hydrogen; D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹b2), wherein each L² is selected from halogen,N-hydroxysuccinimidyl, substituted N-hydroxysuccinimidyl, phenol-yl, andsubstituted phenol-yl, and each R⁸ and R⁹ is independently selected fromhydrogen, C₁₋₄ alkyl, and C₆₋₁₀ aryl; each X¹ and X³ is independentlyselected from a covalent bond, methane-diyl, ethane-1,2-diyl,propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl,heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl,undecane-1,11-diyl, dodecane-1,12-diyl, hexadecane-1,16-diyl,benzene-diyl, methylbenzene-diyl, propylbenzene-diyl,methylcyclohexane-diyl, and —(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—,wherein each n1 and n3 is independently an integer selected from 0 to 5,and each n2 is independently an integer selected from 1 to 25; each X²is selected from a covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—,—C(O), —C(O)O—, —C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ andR² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; Dis selected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹b2), wherein each L² is selected from halogen,N-hydroxysuccinimidyl, substituted N-hydroxysuccinimidyl, phenol-yl, andsubstituted phenol-yl, and each R⁸ and R⁹ is independently selected fromhydrogen, C₁₋₄ alkyl, and C₆₋₁₀ aryl; each X¹ and X³ is independentlyselected from a covalent bond, methane-diyl, ethane-1,2-diyl,propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl,heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl,undecane-1,11-diyl, dodecane-1,12-diyl, hexadecane-1,16-diyl,benzene-diyl, methylbenzene-diyl, propylbenzene-diyl,methylcyclohexane-diyl, and —(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—,wherein each n1 and n3 is independently an integer selected from 0 to 3,and each n2 is independently an integer selected from 1 to 20; each X²is selected from a covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—,and —C(O)N—; each R¹ and R² is independently selected from hydrogen,C₁₋₄ alkyl, and C₆₋₈ aryl; D is selected from a therapeutic agent havingat least one primary amine group and a therapeutic agent having at leastone secondary amine group; and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹b2), wherein each L² is N-hydroxysuccinimidyl, andeach R⁸ and R⁹ is hydrogen; each X¹ is ethane-1,2-diyl; each X² is acovalent bond; each X³ is a covalent bond; each R¹ and R² is hydrogen; Dis selected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹c1); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is selected froma covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ and R² isindependently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; D isselected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹c1); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —C(O)—, —C(O)O—, and —C(O)N—; each R¹ andR² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; Dis selected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹c1); each X¹ is butane-1,4-diyl; each X² is acovalent bond; each X³ is a covalent bond; each R¹ is hydrogen; each R²is methyl; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹c1); each X¹ is butane-1,4-diyl; each X² is—C(O)N—; each X³ is pentane-1,5-diyl; each R¹ and R² is hydrogen; D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹c2); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is selected froma covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ and R² isindependently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; D isselected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹c2); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —C(O)—, —C(O)O—, and —C(O)N—; each R¹ andR² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; Dis selected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹c2); each X¹ is butane-1,4-diyl; each X² is acovalent bond; each X³ is a covalent bond; each R¹ is hydrogen; each R²is methyl; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹c2); each X¹ is butane-1,4-diyl; each X² is—C(O)N—; each X³ is pentane-1,5-diyl; each R¹ is hydrogen; each R² ishydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹c2); each X¹ is butane-1,4-diyl; each X² is—C(O)N—; each X³ is 4-methylcyclohexane-diyl; each R¹ is hydrogen; eachR² is methyl; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹c3); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is selected froma covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ and R² isindependently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; D isselected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹c3); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —C(O)—, —C(O)O—, and —C(O)N—; each R¹ andR² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; Dis selected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹c3); each X¹ is butane-1,4-diyl; each X² is acovalent bond; each X³ is a covalent bond; each R¹ is hydrogen; each R²is methyl; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹c3); each X¹ is butane-1,4-diyl; each X² is—C(O)N—; each X³ is pentane-1,5-diyl; each R¹ is hydrogen; each R² ishydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹c3); each X¹ is butane-1,4-diyl; each X² is—C(O)N—; each X³ is 4-methylcyclohexane-diyl; each R¹ is hydrogen; eachR² is methyl; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹d1); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is selected froma covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ and R² isindependently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; D isselected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹d1); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈aryl; D is selected from a therapeutic agent having at least one primaryamine group and a therapeutic agent having at least one secondary aminegroup; and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹d1); each X¹ is propane-1,3-diyl; each X² is acovalent bond; each X³ is a covalent bond; each R¹ is hydrogen; each R²is hydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹d1); each X¹ is propane-1,3-diyl; each X² is—C(O)N—; each X³ is pentane-1,5-diyl; each R¹ is hydrogen; each R² ishydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹d1); each X¹ is propane-1,3-diyl; each X² is—C(O)N—; each X³ is 4-methylcyclohexane-diyl; each R¹ is hydrogen; eachR² is methyl; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹d2); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is selected froma covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ and R² isindependently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; D isselected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹d2); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈aryl; D is selected from a therapeutic agent having at least one primaryamine group and a therapeutic agent having at least one secondary aminegroup; and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹d2); each X¹ is ethane-1,2-diyl; each X² is acovalent bond; each X³ is a covalent bond; each R¹ is hydrogen; each R²is hydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹d2); each X¹ is ethane-1,2-diyl; each X² is—C(O)N—; each X³ is pentane-1,5-diyl; each R¹ is hydrogen; each R² ishydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹d2); each X¹ is ethane-1,2-diyl; each X² is—C(O)N—; each X³ is 4-methylcyclohexane-diyl; each R¹ is hydrogen; eachR² is hydrogen; D is selected from a therapeutic agent having at leastone primary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹d3); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is selected froma covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ and R² isindependently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; D isselected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹d3); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —C(O)—, —C(O)O—, and —C(O)N—; each R¹ andR² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; Dis selected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹d3); each X¹ is a covalent bond; each X² is acovalent bond; each X³ is a covalent bond; each R¹ is hydrogen; each R²is hydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹d3); each X¹ is a covalent bond; each X² is—C(O)N—; each X³ is pentane-1,5-diyl; each R¹ is hydrogen; each R² ishydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹d3); each X¹ is a covalent bond; each X² is—C(O)N—; each X³ is 4-methylcyclohexane-diyl; each R¹ is hydrogen; eachR² is methyl; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹e1); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is selected froma covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ and R² isindependently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; D isselected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹e1); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —C(O)—, —C(O)O—, and —C(O)N—; each R¹ andR² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; Dis selected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹e1); each X¹ is pentane-1,5-diyl; each X² is acovalent bond; each X³ is a covalent bond; each R¹ is hydrogen; each R²is hydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹e1); each X¹ is pentane-1,5-diyl; each X² is—C(O)N—; each X³ is pentane-1,5-diyl; each R¹ is hydrogen; each R² ishydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹e1); each X¹ is pentane-1,5-diyl; each X² is—C(O)N—; each X³ is 4-methylcyclohexane-diyl; each R¹ is hydrogen; eachR² is methyl; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹f1); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is selected froma covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ and R² isindependently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; D isselected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹f1); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈aryl; D is selected from a therapeutic agent having at least one primaryamine group and a therapeutic agent having at least one secondary aminegroup; and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹f1); each X¹ is a covalent bond; each X² is acovalent bond; each X³ is a covalent bond; each R¹ is hydrogen; each R²is hydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹f1); each X¹ is methane-diyl; each X² is a covalentbond; each X³ is a covalent bond; each R¹ is hydrogen; each R² ishydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹f1); each X¹ is a covalent bond; each X² is—C(O)N—; each X³ is pentane-1,5-diyl; each R¹ is hydrogen; each R² ismethyl; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹f1); each X¹ is a covalent bond; each X² is—C(O)N—; each X³ is 4-methylcyclohexane-diyl; each R¹ is hydrogen; eachR² is methyl; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹f1); each X¹ is pentane-1,5-diyl; each X² is—C(O)N—; each X³ is pentane-1,5-diyl; each R¹ is hydrogen; each R² ismethyl; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹f2); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is selected froma covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ and R² isindependently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; D isselected from a therapeutic agent having at least one primary aminegroup, a therapeutic agent having at least one secondary amine group, atherapeutic agent having at least one hydroxy group, and a therapeuticagent having at least one thiol group; and n5 is selected from 1 to 20.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of (A¹f2); each X¹ and X³ is independently selected from acovalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl,butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl,octane-1,8-diyl, nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —C(O)—, —C(O)O—, and —C(O)N—; each R¹ andR² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl; Dis selected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n5 is selected from 1 to 5.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹f2); each X¹ is methane-diyl; each X² is a covalentbond; each X³ is a covalent bond; each R¹ is hydrogen; each R² ishydrogen; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹f2); each X¹ is methane-diyl; each X² is —C(O)N—;each X³ is pentane-1,5-diyl; each R¹ is hydrogen; each R² is methyl; Dis selected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), each A¹ is amoiety of Formula (A¹f2); each X¹ is methane-diyl; each X² is —C(O)N—;each X³ is 4-methylcyclohexane-diyl; each R¹ is hydrogen; each R² ismethyl; D is selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n5 is selected from 1 to 4.

In certain embodiments of a compound of Formula (II), the compound isselected from a compound of Formula (II-a), Formula (II-b), Formula(II-c), Formula (II-d), Formula (II-e), Formula (II-f), Formula (II-g),Formula (II-h), Formula (II-i), Formula (II-j), Formula (II-k), Formula(II-l), Formula (II-m), Formula (II-n), Formula (II-o), Formula (II-p),Formula (II-q), Formula (II-r), Formula (II-s), Formula (II-t), Formula(II-u), Formula (II-v), Formula (II-w), Formula (II-x), Formula (II-y),Formula (II-z), Formula (II-aa), Formula (II-ab), and Formula (II-ac),or a salt of any of the foregoing:

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-a) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-b) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-c) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-d) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-e) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-f) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-g) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-h) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-i) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-j) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-k) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-l) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-m) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-n) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-o) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-p) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-q) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-r) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-s) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-t) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-u) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-v) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-w) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-x) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-y) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-z) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-aa) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-ab) or a salt thereof.

In certain embodiments, a compound of Formula (II) is a compound ofFormula (II-ac) or a salt thereof.

In certain embodiments, conjugates have the structure of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

Q is selected from a ligand having at least one thiol group, a ligandhaving at least one primary amine group, a ligand having at least onesecondary amine group, a ligand having at least one biotin-bindinggroup, a ligand having at least one photoreactive group, a ligand havingat least one alkyne group, and a ligand having at least one azide group;

each Y is independently selected from a covalent bond and a hydrogenbond;

each A² is independently selected from a covalent bond, an amide group,an avidin-binding group, a carbamate group, a carbonyl group, adisulfide group, an ester group, a hydrazone group, an imine group, asuccinimide group, a sulfonamide group, a sulfone group, a sulfoxidegroup, a thioether group, a triazole group, and a urea group;

each X¹ and X³ is independently selected from a covalent bond, C₁₋₂₀alkanediyl, substituted C₁₋₂₀ alkanediyl, C₁₋₂₀ heteroalkanediyl,substituted C₁₋₂₀ heteroalkanediyl, C₃₋₁₂ cycloalkanediyl, substitutedC₃₋₁₂ cycloalkanediyl, C₃₋₁₂ heterocycloalkanediyl, substituted C₃₋₁₂heterocycloalkanediyl, C₄₋₂₀ alkanecycloalkanediyl, substituted C₄₋₂₀alkanecycloalkanediyl, C₄₋₂₀ heteroalkanecycloalkanediyl, substitutedC₄₋₂₀ heteroalkanecycloalkanediyl, C₆₋₂₀ arenediyl, substituted C₆₋₂₀arenediyl, C₆₋₂₀ heteroarenediyl, substituted C₆₋₂₀ heteroarenediyl,C₇₋₂₀ alkanearenediyl, substituted C₇₋₂₀ alkanearenediyl, C₆₋₂₀heteroalkanearenediyl, substituted C₆₋₂₀ heteroalkanearenediyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein:

-   -   each n1 and n3 is independently an integer selected from 0 to 5;        and    -   each n2 is independently an integer selected from 1 to 25;

each X² is independently selected from a covalent bond, —O—, —S—, —N—,—N═, —N═N—, —N═C—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—, —C(O)N—,—C(O)S—, —C(O)N—N═, —OP(O)(OH)O—, —OC(O)O—, —OC(O)N—, —NC(O)N—, and—NC(S)N;

each R¹ and R² is independently selected from hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆ heteroalkyl,C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₆₋₁₀ heteroaryl, and substitutedC₆₋₁₀ heteroaryl;

each D is independently selected from therapeutic agent having at leastone primary amine group, a therapeutic agent having at least onesecondary amine group, a therapeutic agent having at least one hydroxygroup, and a therapeutic agent having at least one thiol group; and

n6 is an integer selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a ligandhaving at least one thiol group, in certain embodiments at least oneprimary amine group, in certain embodiments at least one secondary aminegroup, in certain embodiments at least one biotin-binding group, incertain embodiments at least one photoreactive group, in certainembodiments at least one alkyne group, and in certain embodiments atleast one azide group.

In certain embodiments of a compound of Formula (III), the ligand isselected from a peptide, a protein, a pegylated protein, a fusionprotein, an antibody, an antibody fragment, a polymer, a copolymer, anda lipid.

In certain embodiments of a compound of Formula (III), the ligand havingat least one thiol group is selected from a peptide, a protein, apegylated protein, a fusion protein, an antibody, an antibody fragment,a polymer, a copolymer, and a lipid.

In certain embodiments of a compound of Formula (III), the ligand havingat least one primary amine group is selected from a peptide, a protein,a pegylated protein, a fusion protein, an antibody, an antibodyfragment, a polymer, a copolymer, and a lipid.

In certain embodiments of a compound of Formula (III), the ligand havingat least one secondary amine group is selected from a peptide, aprotein, a pegylated protein, a fusion protein, an antibody, an antibodyfragment, a polymer, a copolymer, and a lipid.

In certain embodiments of a compound of Formula (III), the ligand havingat least one biotin-binding group is selected from a peptide and aprotein.

In certain embodiments of a compound of Formula (III), the ligand havingat least one biotin-binding group is selected from avidin,deglycosylated avidin, streptavidin, and strep-Tactin.

In certain embodiments of a compound of Formula (III), the ligand havingat least one primary photoreactive group is selected from a peptide, aprotein, a pegylated protein, a fusion protein, an antibody, an antibodyfragment, a polymer, a copolymer, and a lipid.

In certain embodiments of a compound of Formula (III), the ligand havingat least one primary alkyne group is selected from a peptide, a protein,a pegylated protein, a fusion protein, an antibody, an antibodyfragment, a polymer, a copolymer, and a lipid.

In certain embodiments of a compound of Formula (III), the ligand havingat least one primary azide group is selected from a peptide, a protein,a pegylated protein, a fusion protein, an antibody, an antibodyfragment, a polymer, a copolymer, and a lipid.

In certain embodiments of a compound of Formula (III), the ligand is apeptide and is selected from glutathione, carnosine, and pantetheine.

In certain embodiments of a compound of Formula (III), the ligand is aprotein and is selected from bovine serum albumin, human serum albumin,and lactosaminated human serum albumin.

In certain embodiments of a compound of Formula (III), the ligand is aprotein and is selected from avidin, deglycosylated avidin,streptavidin, and strep-Tactin.

In certain embodiments of a compound of Formula (III), the ligand is aprotein and is selected from interferon alfa, interferon alfa-2a,interferon alfa-2b, interferon beta, interferon beta-1a, interferonbeta-1b, interferon gamma, and interferon gamma-1b.

In certain embodiments of a compound of Formula (III), the ligand is apegylated protein and is selected from pegylated interferon alfa,pegylated interferon alfa-2a, pegylated interferon alfa-2b, pegylatedinterferon beta, pegylated interferon beta-1a, pegylated interferonbeta-1b, pegylated interferon gamma, and pegylated interferon gamma-1b.

In certain embodiments of a compound of Formula (III), the ligand is anantibody and is selected from a humanized monoclonal antibody, a murinemonoclonal antibody, a chimeric monoclonal antibody, and a humanmonoclonal antibody.

In certain embodiments of a compound of Formula (III), the ligand is anantibody and is selected from abagovomab, abatacept, abciximab,adalimumab, adecatumumab, afelimomab, alefacept, aflibercept,afutuzumab, alacizumab pegol, alefacept, alemtuzumab, anakinra,anatumomab, anrukinzumab, apolizumab, arcitumomab, aselizumab,atacicept, atorolimumab, baminercept, bapineuzumab, basiliximab,bavituximab, bectumomab, belatacept, belimumab, benralizumab,bertilimumab, besilesomab, bevacizumab, biciromab, bifarcept,blinatumomab, brentuximab, briakinumab, briobacept, canakinumab,catumaxomab, cantuzumab, cedelizumab, certolizumab, certolizumab pegol,cetuximab, cintredekin, cintredekin besudotox, citatuzumab, citatuzumabbogatox, cixutumumab, clenoliximab, clivatuzumab, conatumumab,dacetuzumab, dacliximab, daclizumab, dalotuzumab, daratumumab,denileukin diftitox, denosumab, detumomab, dorlixizumab, drozitumab,ecromeximab, eculizumab, edrecolomab, efalizumab, efungumab,ensituximab, efalizumab, elotuzumab, elsilimomab, enlimomab, enlimomabpegol, epitumomab, epitumomab, epitumomab cituxetan, epratuzumab,erlizumab, ertumaxomab, etanercept, etaracizumab, exbivirumab,fanolesomab, faralimomab, farletuzumab, felvizumab, fezakinumab,figitumumab, fontolizumab, foralumab, foravirumab, fresolimumab,galiximab, ganitumab, gantenerumab, gantenerumab, gavilimomab,gemtuzumab, girentuximab, glembatumumab, golimumab, gomiliximab,ibalizumab, ibritumomab, ibritumomab tiuxetan, igovomab, imciromab,infliximab, inolimomab, inotuzumab, intetumumab, ipilimumab, itolizumab,keliximab, labetuzumab, lebrikizumab, lemalesomab, lenercept,lerdelimumab, lexatumumab, libivirumab, lintuzumab, lorvotuzumab,lucatumumab, lumiliximab, mapatumumab, maslimomab, matuzumab,mavrilimumab, mepolizumab, metelimumab, milatuzumab, minretumomab,mirococept, mitumomab, morolimumab, motavizumab, moxetumomab,moxetumomab pasudotox, muromonab-CD3, nacolomab, nacolomab tafenatox,naptumomab, naptumomab estafenatox, natalizumab, nebacumab, necitumumab,nerelimomab, nimotuzumab, ocrelizumab, odulimomab, ofatumumab,olaratumab, olokizumab, omalizumab, oportuzumab, oportuzumab monatox,oregovomab, otelixizumab, oxelumab, pagibaximab, palivizumab,panitumumab, panobacumab, pascolizumab, pegsunercept, pertuzumab,pexelizumab, pintumomab, priliximab, pritumumab, racotumomab,rafivirumab, ramucirumab, ranibizumab, raxibacumab, regavirumab,reslizumab, rilonacept, rilotumumab, rituximab, robatumumab, roledumab,rontalizumab, rovelizumab, ruplizumab, samalizumab, satumomab,secukinumab, sevirumab, sibrotuzumab, sifalimumab, siltuximab,siplizumab, solanezumab, sontuzumab, sotatercept, stamulumab, sulesomab,suvizumab, tacatuzumab, tadocizumab, talizumab, tanezumab, taplitumomab,taplitumomab paptox, tefibazumab, telimomab, telimomab aritox,teneliximab, tenatumomab, teplizumab, teprotumumab, ticilimumab,tigatuzumab, tocilizumab, toralizumab, tositumomab, tralokinumab,trastuzumab, tremelimumab, tucotuzumab, tucotuzumab celmoleukin,tuvirumab, urtoxazumab, ustekinumab, vapaliximab, vedolizumab,veltuzumab, vepalimomab, visilizumab, volociximab, votumumab,zalutumumab, zanolimumab, ziralimumab, zolimomab, zolimomab aritox.

In certain embodiments of a compound of Formula (III), the ligand is apolymer and is selected from polyethylene glycol (PEG), monomethylpolyethylene glycol (MPEG), polypropylene glycol (PPG), polystyrene, andpolylactide.

In certain embodiments of a compound of Formula (III), the ligand is acopolymer and is selected from N-(2-hydroxypropyl)methacrylamide (HPMA)copolymer and poly(styrene-co-maleic acid).

In certain embodiments of a compound of Formula (III), the ligand isMPEG having a number average molecular weight from about 100 Daltons toabout 60,000 Daltons. In certain embodiments of a compound of Formula(III), the ligand is MPEG having a number average molecular weight fromabout 1,000 Daltons to about 40,000 Daltons. In certain embodiments of acompound of Formula (III), the ligand is MPEG having a number averagemolecular weight from about 1,000 Daltons to about 12,500 Daltons.

In certain embodiments of a compound of Formula (III), the ligand is alipid and is selected from C₈₋₂₀ alkyl.

In certain embodiments of a compound of Formula (III), each Y is thesame, and in certain embodiments, at least some Y are different.

In certain embodiments of a compound of Formula (III), each A² is thesame, and in certain embodiments, at least some A² are different.

In certain embodiments of a compound of Formula (III), each X¹ is thesame, and in certain embodiments, at least some X¹ are different.

In certain embodiments of a compound of Formula (III), each X² is thesame, and in certain embodiments, at least some X² are different.

In certain embodiments of a compound of Formula (III), each X³ is thesame, and in certain embodiments, at least some X³ are different.

In certain embodiments of a compound of Formula (III), each R¹ is thesame, and in certain embodiments, at least some R¹ are different.

In certain embodiments of a compound of Formula (III), each R² is thesame, and in certain embodiments, at least some R² are different.

In certain embodiments of a compound of Formula (III), each D is thesame, and in certain embodiments, at least some D are different.

In certain embodiments of a compound of Formula (III), each group withinthe bracket is the same, and in certain embodiments, at least one groupwithin the brackets is different.

In certain embodiments of a compound of Formula (III), each Y isindependently selected from a covalent bond and a hydrogen bond.

In certain embodiments of a compound of Formula (III), each Y is acovalent bond to the at least one thiol group. In certain embodiments ofa compound of Formula (III), each Y is a covalent bond to the at leastone primary amine group. In certain embodiments of a compound of Formula(III), each Y is a covalent bond to the at least one secondary aminegroup. In certain embodiments of a compound of Formula (III), each Y isa covalent bond to the at least one photoreactive group. In certainembodiments of a compound of Formula (III), each Y is a covalent bond tothe at least one triazole group. In certain embodiments of a compound ofFormula (III), each Y is a covalent bond to the at least one succinimidegroup. In certain embodiments of a compound of Formula (III), each Y isa hydrogen bond to the at least one biotin-binding group.

In certain embodiments of a compound of Formula (III), each A² isindependently selected from a covalent bond, an amide group, anavidin-binding group, a carbamate group, a carbonyl group, a disulfidegroup, an ester group, a hydrazone group, an imine group, a succinimidegroup, a sulfonamide group, a sulfone group, a sulfoxide group, athioether group, a triazole group, and a urea group.

In certain embodiments of a compound of Formula (III), each A² isindependently selected from a covalent bond, —C(O)N—, —C(O)O—, —C═N—,—C(O)N—N═C—, —OC(O)N—, —NC(O)N—, —SO₂—, —SO₂N—, —S—, —SS—, a moiety ofFormula (A²a1), a moiety of Formula (A²b2), a moiety of Formula (A²c1),a moiety of Formula (A²c2), a moiety of Formula (A²c3), a moiety ofFormula (A²f1), and a moiety of Formula (A²f2):

wherein each R⁸ and R⁹ is independently selected from hydrogen, C₁₋₄alkyl, substituted C₁₋₄ alkyl, C₁₋₄ heteroalkyl, substituted C₁₋₄heteroalkyl, C₆₋₁₀ aryl, substituted C₆₋₁₀ aryl, C₆₋₁₀ heteroaryl, andsubstituted C₆₋₁₀ heteroaryl.

In certain embodiments of a compound of Formula (III), each A² is athioether group and is independently selected from —S— and a moiety ofFormula (A²a1).

In certain embodiments of a compound of Formula (III), each A² is anamide group and is independently selected from —C(O)N— and a moiety ofFormula (A²b2).

In certain embodiments of a compound of Formula (III), each A² is anavidin-binding group and is independently selected from a moiety ofFormula (A²c1), a moiety of Formula (A²c2), and a moiety of Formula(A²c3).

In certain embodiments of a compound of Formula (III), each A² is atriazole group and is independently selected from a moiety of Formula(A²f1) and a moiety of Formula (A²f2).

In certain embodiments of a compound of Formula (III), each A² isFormula (A²a1). In certain embodiments of a compound of Formula (III),each A² is Formula (A²a1), wherein each R⁸ and R⁹ is independentlyselected from hydrogen, C₁₋₄ alkyl and C₆₋₈ aryl; in certainembodiments, each R⁸ and R⁹ is independently selected from hydrogen,C₁₋₂ alkyl, and C₆ aryl; and in certain embodiments, each R⁸ and R⁹ ishydrogen.

In certain embodiments of a compound of Formula (III), each A² isFormula (A²b2). In certain embodiments of a compound of Formula (III)wherein each A² is Formula (A²b2), each R⁸ and R⁹ is independentlyselected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl. In certainembodiments of a compound of Formula (III) wherein each A² is Formula(A²b2), each R⁸ and R⁹ is independently selected from hydrogen, methyl,ethyl, propyl, isopropyl, and phenyl. In certain embodiments of acompound of Formula (III) wherein each A² is Formula (A²b2), each R⁸ andR⁹ is hydrogen.

In certain embodiments of a compound of Formula (III), each A² isFormula (A²c1). In certain embodiments of a compound of Formula (III),each A² is Formula (A²c2). In certain embodiments of a compound ofFormula (III), each A² is Formula (A²c3). In certain embodiments of acompound of Formula (III), each A² is Formula (A²f1). In certainembodiments of a compound of Formula (III), each A² is Formula (A²f2).

In certain embodiments of a compound of Formula (III), each X¹ and X³ isindependently selected from a covalent bond, C₁₋₂₀ alkanediyl,substituted C₁₋₂₀ alkanediyl, C₃₋₁₂ cycloalkanediyl, substituted C₃₋₁₂cycloalkanediyl, substituted C₃₋₁₂ heterocycloalkanediyl, C₆₋₂₀arenediyl, substituted C₆₋₂₀ arenediyl, C₇₋₂₀ alkanearenediyl,substituted C₇₋₂₀ alkanearenediyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5 and each n2 isindependently an integer selected from 1 to 25.

In certain embodiments of a compound of Formula (III), each X¹ and X³ isindependently selected from a covalent bond, C₁₋₁₆ alkanediyl,substituted C₁₋₁₆ alkanediyl, C₃₋₆ cycloalkanediyl, benzene-diyl,substituted benzene-diyl, C₇₋₉ benzenealkane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5 and each n2 isindependently an integer selected from 1 to 20.

In certain embodiments of a compound of Formula (III), each X¹ and X³ isindependently selected from a covalent bond, C₁₋₈ alkanediyl,substituted C₁₋₈ alkanediyl, C₃₋₈ cycloalkanediyl, benzene-diyl,substituted benzene-diyl, C₇₋₉ benzenealkane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3 and each n2 isindependently an integer selected from 1 to 10.

In certain embodiments of a compound of Formula (III), each X¹ isselected from C₁₋₂₀ alkanediyl, C₁₋₂₀ cycloalkanediyl, C₆₋₁₀ arenediyl,and C₇₋₂₀ alkanearenediyl. In certain embodiments of a compound ofFormula (III), each X³ is selected from C₁₋₂₀ alkanediyl, C₋₂₀cycloalkanediyl, C₆₋₁₀ arenediyl, and C₇₋₂₀ alkanearenediyl.

In certain embodiments of a compound of Formula (III), each X¹ is acovalent bond.

In certain embodiments of a compound of Formula (III), each X³ is acovalent bond.

In certain embodiments of a compound of Formula (III), each X¹ and X³ isindependently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3 and each n2 isindependently an integer selected from 1 to 20.

In certain embodiments of a compound of Formula (III), each X¹ and X³ isindependently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, pentane-1,5-diyl,4-methylcyclohexane-diyl, benzene-1,2-diyl, benzene-1,3-diyl, andbenzene-1,4-diyl.

In certain embodiments of a compound of Formula (III), each X¹ is acovalent bond; and each X³ is selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, pentane-1,5-diyl,4-methylcyclohexane-diyl, benzene-1,2-diyl, benzene-1,3-diyl, andbenzene-1,4-diyl.

In certain embodiments of a compound of Formula (III), each X¹ isethane-1,2-diyl; and each X³ is selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, pentane-1,5-diyl,4-methylcyclohexane-diyl, benzene-1,2-diyl, benzene-1,3-diyl, andbenzene-1,4-diyl.

In certain embodiments of a compound of Formula (III), each X¹ ispentane-1,5-diyl; and each X³ is selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, pentane-1,5-diyl,4-methylcyclohexane-diyl, benzene-1,2-diyl, benzene-1,3-diyl, andbenzene-1,4-diyl.

In certain embodiments of a compound of Formula (III), each X¹ is4-methylcyclohexane-diyl; and X³ is selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, pentane-1,5-diyl,4-methylcyclohexane-diyl, benzene-1,2-diyl, benzene-1,3-diyl, andbenzene-1,4-diyl.

In certain embodiments of a compound of Formula (III) wherein each X¹and/or X³ is —(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, each n1 and n3 isindependently an integer selected from 0 to 5, an integer selected from0 to 4, an integer selected from 0 to 3, and in certain embodiments, aninteger selected from 0 to 2. In certain embodiments of a compound ofFormula (III) wherein each X¹ and/or X³ is—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, each n2 is independently aninteger selected from 1 to 25, an integer selected from 1 to 20, aninteger selected from 1 to 15, an integer selected from 1 to 10, aninteger selected from 1 to 5, an integer selected from 1 to 4, and incertain embodiments, an integer selected from 1 to 3.

In certain embodiments of a compound of Formula (III), each n1 and n3 isindependently an integer selected from 0 to 5, in certain embodiments,an integer selected from 0 to 4, and in certain embodiments, an integerselected from 0 to 3; and each n2 is independently an integer selectedfrom 1 to 25, in certain embodiments an integer selected from 1 to 20,in certain embodiments an integer selected from 1 to 15, in certainembodiments an integer selected from 1 to 10, and in certain embodimentsan integer selected from 1 to 5.

In certain embodiments of a compound of Formula (III), each X² isselected from a covalent bond, —O—, —S—, —N—, —N═, —N═N—, —N═C—, —SO—,—SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—, —C(O)N—, —C(O)S—, —C(O)N—N═,—OP(O)(OH)O—, —OC(O)O—, —OC(O)N—, —NC(O)N—, and —NC(S)N. In certainembodiments of a compound of Formula (III), each X² is selected from acovalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—, —C(O)—, —C(O)O—,—C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—. In certain embodiments of acompound of Formula (III), each X² is selected from a covalent bond,—SO₂—, —SO₂N—, and —C(O)N—.

In certain embodiments of a compound of Formula (III), each R¹ and R² isindependently selected from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆ heteroalkyl, C₆₋₁₀ aryl,substituted C₆₋₁₀ aryl, C₆₋₁₀ heteroaryl, and substituted C₆₋₁₀heteroaryl.

In certain embodiments of a compound of Formula (III), each R¹ and R² isindependently selected from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆alkyl, and C₆₋₁₀ aryl. In certain embodiments of a compound of Formula(III), R¹ and R² are independently selected from hydrogen, methyl,ethyl, propyl, isopropyl, and phenyl. In certain embodiments of acompound of Formula (III), each R¹ and R² is independently selected fromhydrogen and methyl. In certain embodiments of a compound of Formula(III), each R¹ and R² is independently selected from hydrogen and ethyl.In certain embodiments of a compound of Formula (III), each R¹ and R² isindependently selected from hydrogen and propyl. In certain embodimentsof a compound of Formula (III), each R¹ and R² is independently selectedfrom hydrogen and isopropyl. In certain embodiments of a compound ofFormula (III), each R¹ and R² is independently selected from hydrogenand phenyl.

In certain embodiments of a compound of Formula (III), each R¹ and R² ishydrogen. In certain embodiments of a compound of Formula (III), each R¹is hydrogen and each R² is methyl. In certain embodiments of a compoundof Formula (III), each R¹ is hydrogen and each R² is ethyl. In certainembodiments of a compound of Formula (III), each R¹ is hydrogen and eachR² is propyl. In certain embodiments of a compound of Formula (III),each R¹ is hydrogen and each R² is isopropyl. In certain embodiments ofa compound of Formula (III), each R¹ is hydrogen and each R² is phenyl.

In certain embodiments of a compound of Formula (III), each D isindependently selected from a therapeutic agent having at least oneprimary amine group, a therapeutic agent having at least one secondaryamine group, a therapeutic agent having at least one hydroxy group, anda therapeutic agent having at least one thiol group.

In certain embodiments of a compound of Formula (III), each D isindependently selected from a folic acid analog, a purine analog, apyrimidine analog, an anthracycline derivative, a dolastatin derivative,a camptotheca derivative, an ectainascidin derivative, a colchicinederivative, a duocarmycin derivative, an enediyne derivative, anepothilone derivative, a halichondrin derivative, a kahalalidederivative, a streptomyces, a tubulysin derivative, a vinca alkaloid, anantifolate, a hemiasterlin, a cathepsin K inhibitor, dipeptidylpeptidase IV inhibitor, heat shock protein 90 (Hsp90) inhibitor, ahistone deacetylase inhibitor, an immunomodulator, an aurora kinaseinhibitor, a cyclin-dependent kinase inhibitor, tyrosine kinaseinhibitor, kinesin-related motor protein Eg5 inhibitor, kinesin spindleprotein inhibitor, microtubule interference compounds, topoisomeraseinhibitor, and an antibiotic.

In certain embodiments of a compound of Formula (III), each D isindependently selected from aminopterin, folitixorin, methotrexate,pemetrexed, pralatrexate, raltitrexed, pelitrexol, talotrexin,deoxycoformycin, cladribine, clofarabine, fludarabine, thioguanine,mercaptopurine, berubicin, daunorubicin, doxorubicin, epirubicin,idarubicin, amrubicin, pirarubicin, zorubicin, mitoxantrone,banoxantrone, ledoxantrone, nortopixantrone, pixantrone, piroxantrone,sabarubicin, topixantrone, monomethyl auristatin E, monomethylauristatin F, monomethyl dolastatin 10, dolastatin 15, belotecan,atiratecan, camptothecin, exatecan, irinotecan, namitecan, rubitecan,topotecan, demecolcine, duocarmycin A, duocarmycin SA, duocarmycin B,duocarmycin B1, abbeymycin, anthramycin, centanamycin, chicamycin,mazethramycin, porothramycin A, porothramycin B, sibanomycin,sibiromycin, trabectedin, calicheamicin γ1, calicheamicin T, esperamicinA1, esperamicin C, esperamicin D, dynemicin A, dynemicin H, dynemicin M,dynemicin N, dynemicin O, dynemicin P, dynemicin Q, dynemicin S,neocarzinostatin chromophore, uncialamycin, 21-aminoepothilone B,eribulin, hemiasterlin, HTI-286, kahalatide F, elsamitrucin, lucanthone,melphalan, mitoguazone, nimustine, procarbazine, dacarbazine, amsacrine,5-amino-4-oxo-pentanoic acid, methyl 5-amino-4-oxo-pentanoate,actinomycin D, 7-aminoactinomycin D, bleomycin, mitomycin,staurosporine, desacetylvinblastine hydrazide, vinblastine, vincristine,vindesine, vinflunine, vinorelbine, afatinib, apilimod, balamapimod,barasertib, bosutinib, canertinib, cevipabulin, crizotinib, dacomitinib,dasatinib, denibulin, dilmapimod, dinaciclib, dovitinib, dutacatib,duvoglustat, edotecarin, elisidepsin, entinostat, epetirimod, erlotinib,fingolimod, fostamatinib, gefitinib, golotimod, gusperimus, imatinib,imiquimod, intedanib, ispinesib, lapatinib, lenalidomide, linifanib,litronesib, losmapimod, metesind, mocetinostat, motesanib, masitinib,myriocin, neratinib, nilotinib, odanacatib, ombrabulin, pamapimod,panobinostat, pazopanib, plerixafor, pomalidomide, razupenem,resiquimod, sabarubicin, saracatinib, seliciclib, selumetinib,sotirimod, squalamine, tacedinaline, talabostat, taltobulin, telatinib,tipifarnib, tozasertib, vandetanib, vatalanib, veliparib, voreloxin,alvespimycin, amikacin, amphotericin B, arbekacin, astromicin,bacitracin, balofloxacin, bederocin, bekanamycin, besifloxacin,brodimoprim, ciprofloxacin, clinafloxacin, colistin, daptomycin,dibekacin, enoxacin, framycetin, garenoxacin, gatifloxacin,gemifloxacin, gentamicin, gentamicin, grepafloxacin, hamycin,hexetidine, hygromycin B, ibacitabine, iclaprim, isepamicin,kanamycin,lomefloxacin, lucimycin, lymecycline, mepartricin, moxifloxacin,natamycin, nemonoxacin, neomycin B, neomycin C, netilmicin, norfloxacin,nystatin, omadacycline, oritavancin, paromomycin, pazufloxacin,perimycin A, perimycin B, perimycin C, pipemidic acid, polymyxin B,puromycin, radezolid, retaspimycin, ribostamycin, rimocidin, sisomicin,sitafloxacin, sparfloxacin, spectinomycin, streptomycin, sulfacetamide,sulfadiazine, sulfadimethoxine, sulfadimidine, sulfafurazole, sulfalene,sulfamazone, sulfamerazine, sulfamethizole, sulfamethoxazole,sulfamethoxypyridazine, sulfametomidine, sulfametoxydiazine,sulfametrole, sulfamoxole, sulfanilamide , sulfaperin, sulfaphenazole,sulfapyridine, sulfathiazole, sulfathiourea, sulfisomidine, teicoplanin,telavancin, tanespimycin, temafloxacin, tetroxoprim, tigecycline,tobramycin, tosufloxacin, trimethoprim, trimethoprim, trovafloxacin,tyrothricin, ulifloxacin, valnemulin, vancomycin, verdamicin, andzabofloxacin.

In certain embodiments of a compound of Formula (III), n6 is an integerselected from 1 to 20; in certain embodiments, an integer selected from1 to 10; in certain embodiments, an integer selected from 1 to 4; and incertain embodiments, n6 is 1, 2, 3, or 4. In certain embodiments, n6 is1, n6 is 2, n6 is 3, and in certain embodiments n6 is 4.

In certain embodiments of a compound of Formula (III), Q is a ligandselected from a C₅₋₂₀ alkyl, a polyethylene glycol, an avidin, analbumin, an antibody, a polymer, and a glass (SiO₂) substrate; each Y isindependently selected from a covalent bond and a hydrogen bond; each A²is independently selected from a covalent bond, —C(O)N—, —C(O)O—, —C═N—,—C(O)N—N═C—, —OC(O)N—, —NC(O)N—, —SO₂—, —SO₂N—, —S—, —SS—, a moiety ofFormula (A²a1), a moiety of Formula (A²b2), a moiety of Formula (A²c1),a moiety of Formula (A²c2), a moiety of Formula (A²c3), a moiety ofFormula (A²f1), and a moiety of Formula (A²f2); each X¹ and X³ isindependently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methyl cyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5, and each n2 isindependently an integer selected from 1 to 25; each X² is independentlyselected from a covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂N—, —SS—,—C(O)—, —C(O)O—, —C(O)N—, —C(O)N—N═, —OC(O)N—, and —NC(O)N—; each R¹ andR² is independently selected from hydrogen, C₁₋₄ alkyl, and C₆₋₈ aryl;each D is selected from a therapeutic agent having at least one primaryamine group, a therapeutic agent having at least one secondary aminegroup, a therapeutic agent having at least one hydroxy group, and atherapeutic agent having at least one thiol group; and n6 is selectedfrom 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a ligandselected from a C₅-₂₀ alkyl, an MPEG, a human serum albumin, anantibody, a polymer, and a glass (SiO₂) substrate; each Y isindependently selected from a covalent bond and a hydrogen bond; each A²is independently selected from a covalent bond, —C(O)N—, —SO₂—, —SO₂N—,—S—, —SS—, a moiety of Formula (A²a1), a moiety of Formula (A²b2), amoiety of Formula (A²c1), a moiety of Formula (A²c2), a moiety ofFormula (A²c3), a moiety of Formula (A²f1), and a moiety of Formula(A²f2); each X¹ and X³ is independently selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen, methyl, ethyl,propyl, isopropyl, and phenyl; each D is selected from a therapeuticagent having at least one primary amine group and a therapeutic agenthaving at least one secondary amine group; and n6 is selected from 1 to20.

In certain embodiments of a compound of Formula (III), Q is a C₅₋₂₀alkyl; each Y is a covalent bond; each A² is independently selected froma covalent bond, —C(O)N—, —SO₂—, —S—, a moiety of Formula (A²a1), amoiety of Formula (A²f1), and a moiety of Formula (A²f2); each X¹ and X³is independently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is a C₅-₂₀alkyl; each Y is a covalent bond; each A² is a moiety of Formula (A²a1);each X¹ and X³ is independently selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is a C₅₋₂₀alkyl; each Y is a covalent bond; each A² is a moiety of Formula (A²a1),wherein each R⁸ and R⁹ is hydrogen; each X¹ is pentane-1,5-diyl; each X²is a covalent bond; each X³ is a covalent bond; each R¹ and R² ishydrogen; each D is independently selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n6 is selected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is a C₅₋₂₀alkyl; each Y is a covalent bond; each A² is a moiety of Formula (A²a1),wherein each R⁸ and R⁹ is hydrogen; each X¹ is 4-methylcyclohexane-diyl;each X² is a covalent bond; each X³ is a covalent bond; each R¹ and R²is hydrogen; each D is selected from a therapeutic agent having at leastone primary amine group and a therapeutic agent having at least onesecondary amine group; and n6 is selected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is a C₅₋₂₀alkyl; each Y is a covalent bond; each A² is a moiety of Formula (A²a1),wherein each R⁸ and R⁹ is hydrogen; each X¹ is pentane-1,5-diyl; each X²is —C(O)N—; each X³ is pentane-1,5-diyl; each R¹ and R² is hydrogen;each D is selected from a therapeutic agent having at least one primaryamine group and a therapeutic agent having at least one secondary aminegroup; and n6 is selected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is a C₅₋₂₀alkyl; each Y is a covalent bond; each A² is a moiety of Formula (A²f1);each X¹ and X³ is independently selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is a C₅₋₂₀alkyl; each Y is a covalent bond; each A² is a moiety of Formula (A²f1);each X¹ is pentane-1,5-diyl; each X² is a covalent bond; each X³ is acovalent bond; each R¹ and R² is hydrogen; each D is independentlyselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is a C₅₋₂₀alkyl; each Y is a covalent bond; each A² is a moiety of Formula (A²f1);each X¹ is 4-methylcyclohexane-diyl; each X² is a covalent bond; each X³is a covalent bond; each R¹ and R² is hydrogen; each D is selected froma therapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is a C₅₋₂₀alkyl; each Y is a covalent bond; each A² is a moiety of Formula (A²f1);each X¹ is pentane-1,5-diyl; each X² is —C(O)N—; each X³ ispentane-1,5-diyl; each R¹ and R² is hydrogen; each D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is a C₅₋₂₀alkyl; each Y is a covalent bond; each A² is a moiety of Formula (A²f2);each X¹ and X³ is independently selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is a C₅₋₂₀alkyl; each Y is a covalent bond; each A² is a moiety of Formula (A²f2);each X¹ is methane-diyl; each X² is a covalent bond; each X³ is acovalent bond; each R¹ and R² is hydrogen; each D is independentlyselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is a C₅₋₂₀alkyl; each Y is a covalent bond; each A² is a moiety of Formula (A²f2);each X¹ is methane-diyl; each X² is —C(O)N—; each X³ ispentane-1,5-diyl; each R¹ and R² is hydrogen; each D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is an MPEGhaving a number average molecular weight from about 10,000 to 60,000daltons; each Y is a covalent bond; each A² is independently selectedfrom a covalent bond, —C(O)N—, —SO₂—, —S—, a moiety of Formula (A²a1), amoiety of Formula (A²f1), and a moiety of Formula (A²f2); each X¹ and X³is independently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an MPEGhaving a number average molecular weight from about 10,000 to 60,000daltons; each Y is a covalent bond; each A² is a moiety of Formula(A²a1); each X¹ and X³ is independently selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an MPEGhaving a number average molecular weight from about 10,000 to 60,000daltons; each Y is a covalent bond; each A² is a moiety of Formula(A²a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ is pentane-1,5-diyl;each X² is a covalent bond; each X³ is a covalent bond; each R¹ and R²is hydrogen; each D is independently selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n6 is selected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is an MPEGhaving a number average molecular weight from about 10,000 to 60,000daltons; each Y is a covalent bond; each A² is a moiety of Formula(A²a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ is4-methylcyclohexane-diyl; each X² is a covalent bond; each X³ is acovalent bond; each R¹ and R² is hydrogen; each D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is an MPEGhaving a number average molecular weight from about 10,000 to 60,000daltons; each Y is a covalent bond; each A² is a moiety of Formula(A²a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ is pentane-1,5-diyl;each X² is —C(O)N—; each X³ is pentane-1,5-diyl; each R¹ and R² ishydrogen; each D is selected from a therapeutic agent having at leastone primary amine group and a therapeutic agent having at least onesecondary amine group; and n6 is selected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is an MPEGhaving a number average molecular weight from about 10,000 to 60,000daltons; each Y is a covalent bond; each A² is a moiety of Formula(A²f1); each X¹ and X³ is independently selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an MPEGhaving a number average molecular weight from about 10,000 to 60,000daltons; each Y is a covalent bond; each A² is a moiety of Formula(A²f1); each X¹ is pentane-1,5-diyl; each X² is a covalent bond; each X³is a covalent bond; each R¹ and R² is hydrogen; each D is independentlyselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is an MPEGhaving a number average molecular weight from about 10,000 to 60,000daltons; each Y is a covalent bond; each A² is a moiety of Formula(A²f1); each X¹ is 4-methylcyclohexane-diyl; each X² is a covalent bond;each X³ is a covalent bond; each R¹ and R² is hydrogen; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is an MPEGhaving a number average molecular weight from about 10,000 to 60,000daltons; each Y is a covalent bond; each A² is a moiety of Formula(A²f1); each X¹ is pentane-1,5-diyl; each X² is —C(O)N—; each X³ ispentane-1,5-diyl; each R¹ and R² is hydrogen; each D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is an MPEGhaving a number average molecular weight from about 10,000 to 60,000daltons; each Y is a covalent bond; each A² is a moiety of Formula(A²f2); each X¹ and X³ is independently selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an MPEGhaving a number average molecular weight from about 10,000 to 60,000daltons; each Y is a covalent bond; each A² is a moiety of Formula(A²f2); each X¹ is methane-diyl; each X² is a covalent bond; each X³ isa covalent bond; each R¹ and R² is hydrogen; each D is independentlyselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is an MPEGhaving a number average molecular weight from about 10,000 to 60,000daltons; each Y is a covalent bond; each A² is a moiety of Formula(A²f2); each X¹ is methane-diyl; each X² is —C(O)N—; each X³ ispentane-1,5-diyl; each R¹ and R² is hydrogen; each D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is an avidin;each Y is a hydrogen bond; each A² is independently selected from amoiety of Formula (A²c1), a moiety of Formula (A²c2), and a moiety ofFormula (A²c3); each X¹ and X³ is independently selected from a covalentbond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is an avidin;each Y is a hydrogen bond; each A² is independently selected from amoiety of Formula (A²c1), a moiety of Formula (A²c2), and a moiety ofFormula (A²c3); each X¹ is butane-1,4-diyl; each X² is selected from acovalent bond and —C(O)N—; each X³ is selected from a covalent bond,pentane-1,5-diyl, and —(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, whereineach n1 and n3 is independently an integer selected from 0 to 3, andeach n2 is independently an integer selected from 1 to 10; each R¹ andR² is hydrogen; each D is independently selected from a therapeuticagent having at least one primary amine group and a therapeutic agenthaving at least one secondary amine group; and n6 is selected from 1 to4.

In certain embodiments of a compound of Formula (III), Q is an avidin;each Y is a hydrogen bond; each A² is a moiety of Formula (A²c1); eachX¹ is butane-1,4-diyl; each X² is —C(O)N—; each X³ is pentane-1,5-diyl;each R¹ and R² is hydrogen; each D is independently selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is an avidin;each Y is a hydrogen bond; each A² is a moiety of Formula (A²c2); eachX¹ is butane-1,4-diyl; each X² is —C(O)N—; each X³ is pentane-1,5-diyl;each R¹ and R² is hydrogen; each D is independently selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is an avidin;each Y is a hydrogen bond; each A² is a moiety of Formula (A²c3); eachX¹ is butane-1,4-diyl; each X² is —C(O)N—; each X³ is pentane-1,5-diyl;each R¹ and R² is hydrogen; each D is independently selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 4.

In certain embodiments of a compound of Formula (III), Q is a humanserum albumin; each Y is a covalent bond; each A² is independentlyselected from a covalent bond, —C(O)N—, —SO₂—, —S—, a moiety of Formula(A²a1), a moiety of Formula (A²f1), and a moiety of Formula (A²f2); eachX¹ and X³ is independently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is 1.

In certain embodiments of a compound of Formula (III), Q is a humanserum albumin; each Y is a covalent bond; each A² is a moiety of Formula(A²a1); each X¹ and X³ is independently selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is 1.

In certain embodiments of a compound of Formula (III), Q is a humanserum albumin; each Y is a covalent bond; each A² is a moiety of Formula(A²a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ is pentane-1,5-diyl;each X² is a covalent bond; each X³ is a covalent bond; each R¹ and R²is hydrogen; each D is independently selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n6 is 1.

In certain embodiments of a compound of Formula (III), Q is a humanserum albumin; each Y is a covalent bond; each A² is a moiety of Formula(A²a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ is4-methylcyclohexane-diyl; each X² is a covalent bond; each X³ is acovalent bond; each R¹ and R² is hydrogen; each D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 is1.

In certain embodiments of a compound of Formula (III), Q is a humanserum albumin; each Y is a covalent bond; each A² is a moiety of Formula(A²a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ is pentane-1,5-diyl;each X² is —C(O)N—; each X³ is pentane-1,5-diyl; each R¹ and R² ishydrogen; each D is selected from a therapeutic agent having at leastone primary amine group and a therapeutic agent having at least onesecondary amine group; and n6 is 1.

In certain embodiments of a compound of Formula (III), Q is a humanserum albumin; each Y is a covalent bond; each A² is a moiety of Formula(A²f1); each X¹ and X³ is independently selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is 1.

In certain embodiments of a compound of Formula (III), Q is a humanserum albumin; each Y is a covalent bond; each A² is a moiety of Formula(A²f1); each X¹ is pentane-1,5-diyl; each X² is a covalent bond; each X³is a covalent bond; each R¹ and R² is hydrogen; each D is independentlyselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is 1.

In certain embodiments of a compound of Formula (III), Q is a humanserum albumin; each Y is a covalent bond; each A² is a moiety of Formula(A²f1); each X¹ is 4-methylcyclohexane-diyl; each X² is a covalent bond;each X³ is a covalent bond; each R¹ and R² is hydrogen; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is 1.

In certain embodiments of a compound of Formula (III), Q is a humanserum albumin; each Y is a covalent bond; each A² is a moiety of Formula(A²f1); each X¹ is pentane-1,5-diyl; each X² is —C(O)N—; each X³ ispentane-1,5-diyl; each R¹ and R² is hydrogen; each D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 is1.

In certain embodiments of a compound of Formula (III), Q is an antibody;each Y is a covalent bond; each A² is independently selected from acovalent bond, —C(O)N—, —SO₂—, —S—, a moiety of Formula (A²a1), a moietyof Formula (A²f1), and a moiety of Formula (A²f2); each X¹ and X³ isindependently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an antibody;each Y is a covalent bond; each A² is a moiety of Formula (A²a1); eachX¹ and X³ is independently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an antibody;each Y is a covalent bond; each A² is a moiety of Formula (A²a1),wherein each R⁸ and R⁹ is hydrogen; each X¹ is pentane-1,5-diyl; each X²is a covalent bond; each X³ is a covalent bond; each R¹ and R² ishydrogen; each D is independently selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an antibody;each Y is a covalent bond; each A² is a moiety of Formula (A²a1),wherein each R⁸ and R⁹ is hydrogen; each X¹ is 4-methylcyclohexane-diyl;each X² is a covalent bond; each X³ is a covalent bond; each R¹ and R²is hydrogen; each D is selected from a therapeutic agent having at leastone primary amine group and a therapeutic agent having at least onesecondary amine group; and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an antibody;each Y is a covalent bond; each A² is a moiety of Formula (A²a1),wherein each R⁸ and R⁹ is hydrogen; each X¹ is pentane-1,5-diyl; each X²is —C(O)N—; each X³ is pentane-1,5-diyl; each R¹ and R² is hydrogen;each D is selected from a therapeutic agent having at least one primaryamine group and a therapeutic agent having at least one secondary aminegroup; and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an antibody;each Y is a covalent bond; each A² is a moiety of Formula (A²f1); eachX¹ and X³ is independently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an antibody;each Y is a covalent bond; each A² is a moiety of Formula (A²f1); eachX¹ is pentane-1,5-diyl; each X² is a covalent bond; each X³ is acovalent bond; each R¹ and R² is hydrogen; each D is independentlyselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an antibody;each Y is a covalent bond; each A² is a moiety of Formula (A²f1); eachX¹ is 4-methylcyclohexane-diyl; each X² is a covalent bond; each X³ is acovalent bond; each R¹ and R² is hydrogen; each D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an antibody;each Y is a covalent bond; each A² is a moiety of Formula (A²f1); eachX¹ is pentane-1,5-diyl; each X² is —C(O)N—; each X³ is pentane-1,5-diyl;each R¹ and R² is hydrogen; each D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an antibody;each Y is a covalent bond; each A² is a moiety of Formula (A²f2); eachX¹ and X³ is independently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an antibody;each Y is a covalent bond; each A² is a moiety of Formula (A²f2); eachX¹ is methane-diyl; each X² is a covalent bond; each X³ is a covalentbond; each R¹ and R² is hydrogen; each D is independently selected froma therapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is an antibody;each Y is a covalent bond; each A² is a moiety of Formula (A²f2); eachX¹ is methane-diyl; each X² is —C(O)N—; each X³ is pentane-1,5-diyl;each R¹ and R² is hydrogen; each D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n6 is selected from 1 to 5.

In certain embodiments of a compound of Formula (III), Q is apolystyrene; each Y is a covalent bond; each A² is independentlyselected from a covalent bond, —C(O)N—, —SO₂—, —S—, a moiety of Formula(A²a1), a moiety of Formula (A²f1), and a moiety of Formula (A²f2); eachX¹ and X³ is independently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is apolystyrene; each Y is a covalent bond; each A² is a moiety of Formula(A²a1); each X¹ and X³ is independently selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is apolystyrene; each Y is a covalent bond; each A² is a moiety of Formula(A²a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ is pentane-1,5-diyl;each X² is a covalent bond; each X³ is a covalent bond; each R¹ and R²is hydrogen; each D is independently selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is apolystyrene; each Y is a covalent bond; each A² is a moiety of Formula(A²a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ is4-methylcyclohexane-diyl; each X² is a covalent bond; each X³ is acovalent bond; each R¹ and R² is hydrogen; each D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is apolystyrene; each Y is a covalent bond; each A² is a moiety of Formula(A²a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ is pentane-1,5-diyl;each X² is —C(O)N—; each X³ is pentane-1,5-diyl; each R¹ and R² ishydrogen; each D is selected from a therapeutic agent having at leastone primary amine group and a therapeutic agent having at least onesecondary amine group; and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is apolystyrene; each Y is a covalent bond; each A² is a moiety of Formula(A²f1); each X¹ and X³ is independently selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is apolystyrene; each Y is a covalent bond; each A² is a moiety of Formula(A²f1); each X¹ is pentane-1,5-diyl; each X² is a covalent bond; each X³is a covalent bond; each R¹ and R² is hydrogen; each D is independentlyselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is apolystyrene; each Y is a covalent bond; each A² is a moiety of Formula(A²f1); each X¹ is 4-methylcyclohexane-diyl; each X² is a covalent bond;each X³ is a covalent bond; each R¹ and R² is hydrogen; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is apolystyrene; each Y is a covalent bond; each A² is a moiety of Formula(A²f1); each X¹ is pentane-1,5-diyl; each X² is —C(O)N—; each X³ ispentane-1,5-diyl; each R¹ and R² is hydrogen; each D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is apolystyrene; each Y is a covalent bond; each A² is a moiety of Formula(A²f2); each X¹ and X³ is independently selected from a covalent bond,methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is apolystyrene; each Y is a covalent bond; each A² is a moiety of Formula(A²f2); each X¹ is methane-diyl; each X² is a covalent bond; each X³ isa covalent bond; each R¹ and R² is hydrogen; each D is independentlyselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is apolystyrene; each Y is a covalent bond; each A² is a moiety of Formula(A²f2); each X¹ is methane-diyl; each X² is —C(O)N—; each X³ ispentane-1,5-diyl; each R¹ and R² is hydrogen; each D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a glass(SiO₂) substrate; each Y is a covalent bond; each A² is independentlyselected from a covalent bond, —C(O)N—, —SO₂—, —S—, a moiety of Formula(A²a1), a moiety of Formula (A²f1), and a moiety of Formula (A²f2); eachX¹ and X³ is independently selected from a covalent bond, methane-diyl,ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl,hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl, nonane-1,9-diyl,decane-1,10-diyl, undecane-1,11-diyl, dodecane-1,12-diyl,hexadecane-1,16-diyl, benzene-diyl, methylbenzene-diyl,propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a glass(SiO₂) substrate; each Y is a covalent bond; each A² is a moiety ofFormula (A²a1); each X¹ and X³ is independently selected from a covalentbond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a glass(SiO₂) substrate; each Y is a covalent bond; each A² is a moiety ofFormula (A²a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ ispentane-1,5-diyl; each X² is a covalent bond; each X³ is a covalentbond; each R¹ and R² is hydrogen; each D is independently selected froma therapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a glass(SiO₂) substrate; each Y is a covalent bond; each A² is a moiety ofFormula (A²a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ is4-methylcyclohexane-diyl; each X² is a covalent bond; each X³ is acovalent bond; each R¹ and R² is hydrogen; each D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a glass(SiO₂) substrate; each Y is a covalent bond; each A² is a moiety ofFormula (A²a1), wherein each R⁸ and R⁹ is hydrogen; each X¹ ispentane-1,5-diyl; each X² is —C(O)N—; each X³ is pentane-1,5-diyl; eachR¹ and R² is hydrogen; each D is selected from a therapeutic agenthaving at least one primary amine group and a therapeutic agent havingat least one secondary amine group; and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a glass(SiO₂) substrate; each Y is a covalent bond; each A² is a moiety ofFormula (A²f1); each X¹ and X³ is independently selected from a covalentbond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a glass(SiO₂) substrate; each Y is a covalent bond; each A² is a moiety ofFormula (A²f1); each X¹ is pentane-1,5-diyl; each X² is a covalent bond;each X³ is a covalent bond; each R¹ and R² is hydrogen; each D isindependently selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a glass(SiO₂) substrate; each Y is a covalent bond; each A² is a moiety ofFormula (A²f1); each X¹ is 4-methylcyclohexane-diyl; each X² is acovalent bond; each X³ is a covalent bond; each R¹ and R² is hydrogen;each D is selected from a therapeutic agent having at least one primaryamine group and a therapeutic agent having at least one secondary aminegroup; and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a glass(SiO₂) substrate; each Y is a covalent bond; each A² is a moiety ofFormula (A²f1); each X¹ is pentane-1,5-diyl; each X² is —C(O)N—; each X³is pentane-1,5-diyl; each R¹ and R² is hydrogen; each D is selected froma therapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a glass(SiO₂) substrate; each Y is a covalent bond; each A² is a moiety ofFormula (A²f2); each X¹ and X³ is independently selected from a covalentbond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octane-1,8-diyl,nonane-1,9-diyl, decane-1,10-diyl, undecane-1,11-diyl,dodecane-1,12-diyl, hexadecane-1,16-diyl, benzene-diyl,methylbenzene-diyl, propylbenzene-diyl, methylcyclohexane-diyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 3, and each n2 isindependently an integer selected from 1 to 20; each X² is selected froma covalent bond, —O—, —SO₂—, —SO₂N—, —C(O)—, —C(O)O—, and —C(O)N—; eachR¹ and R² is independently selected from hydrogen and methyl; each D isselected from a therapeutic agent having at least one primary aminegroup and a therapeutic agent having at least one secondary amine group;and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a glass(SiO₂) substrate; each Y is a covalent bond; each A² is a moiety ofFormula (A²f2); each X¹ is methane-diyl; each X² is a covalent bond;each X³ is a covalent bond; each R¹ and R² is hydrogen; each D isindependently selected from a therapeutic agent having at least oneprimary amine group and a therapeutic agent having at least onesecondary amine group; and n6 is selected from 1 to 20.

In certain embodiments of a compound of Formula (III), Q is a glass(SiO₂) substrate; each Y is a covalent bond; each A² is a moiety ofFormula (A²f2); each X¹ is methane-diyl; each X² is —C(O)N—; each X³ ispentane-1,5-diyl; each R¹ and R² is hydrogen; each D is selected from atherapeutic agent having at least one primary amine group and atherapeutic agent having at least one secondary amine group; and n6 isselected from 1 to 20.

The compound of claim 48, wherein the compound is selected from acompound of Formula (III-a), Formula (III-b), Formula (III-c), Formula(III-d), Formula (III-e), Formula (III-f), Formula (III-g), Formula(III-h), Formula (III-i), Formula (III-j), Formula (III-k), Formula(III-l), Formula (III-m), Formula (III-n), Formula (III-o), Formula(III-p), Formula (III-q), Formula (III-r), Formula (III-s), Formula(III-t), Formula (III-u), Formula (III-III), Formula (III-w), Formula(III-x), Formula (III-y), Formula (III-z), Formula (III-aa), Formula(III-ab), and Formula (III-ac), or a pharmaceutically acceptable salt ofany of the foregoing:

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-a) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-b) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-c) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-d) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-e) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-f) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-g) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-h) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-i) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-j) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-k) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-l) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-m) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-n) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-o) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-p) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-q) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-r) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-s) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-t) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-u) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-v) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-w) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-x) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-y) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-z) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-aa) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-ab) or a pharmaceutically acceptable saltthereof.

In certain embodiments of a compound of Formula (III), the compound hasthe structure of Formula (III-ac) or a pharmaceutically acceptable saltthereof.

In certain embodiments, cleavable crosslinkers, when coupled to aprimary or secondary amine-containing compound, are labile under mildbasic conditions. In certain embodiments, a conjugate of Formula (II) orFormula (III) can be cleaved from a primary or secondaryamine-containing compound from about pH 7.4 to about pH 10, from aboutpH 7.4 to about pH 9.0, and in certain embodiments from about pH 7.4 toabout pH 8.5.

Method of Synthesis of Cleavable Drug Conjugates

Cleavable crosslinkers, cleavable crosslinking intermediates, andcleavable conjugates provided by the present disclosure may besysnthesized by methods known to those skilled in the art. For example,methods of synthesizing related acyloxyalkyl carbamate compounds aredescribed by Alexander, U.S. Pat. No. 4,760,057; Alexander, U.S. Pat.No. 4,916,230; Lund, U.S. Pat. No. 5,401,868; Alexander, U.S. Pat. No.5,466,811; Alexander, U.S. Pat. No. 5,684,018; Gallop, U.S. Pat. No.7,227,028, and Singh, PCT Publication No. WO 2005097760.

In certain embodiments, methods of synthesizing conjugates of Formula(II) or Formula (III) comprise (i) mixing a solution containing acompound having at least one primary amine group and/or at least onesecondary amine group (D-NH₂) and a cleavable crosslinker of Formula (I)in dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or an aqueousbuffer (pH 7.0-8.5) such as phosphate buffered saline (PBS) for at least30 minutes at room temperature to obtain the corresponding conjugate ofFormula (II); and (ii) mixing a solution containing the conjugate ofFormula (II) and a ligand having at least one thiol group (Q-SH) indimethylformamide (DMF), dimethyl sulfoxide (DMSO) or an aqueous buffer(pH 7.0-8.5) such as phosphate buffered saline (PBS) for at least 30minutes at room temperature to obtain the corresponding conjugates ofFormula (III) as shown in Scheme A.

In certain embodiments, methods of synthesizing cleavable drugconjugates of Formula (II) and Formula (III) are shown in Schemes 1 to6.

Examples of therapeutic agents having a primary amine group and/or asecondary amine group include aminopterin, folitixorin, methotrexate,pemetrexed, pralatrexate, raltitrexed, pelitrexol, talotrexin,deoxycoformycin, cladribine, clofarabine, fludarabine, thioguanine,mercaptopurine, berubicin, daunorubicin, doxorubicin, epirubicin,idarubicin, amrubicin, pirarubicin, zorubicin, mitoxantrone,banoxantrone, ledoxantrone, nortopixantrone, pixantrone, piroxantrone,sabarubicin, topixantrone, monomethyl auristatin E, monomethylauristatin F, monomethyl dolastatin 10, dolastatin 15, belotecan,atiratecan, camptothecin, exatecan, irinotecan, namitecan, rubitecan,topotecan, demecolcine, duocarmycin A, duocarmycin SA, duocarmycin B,duocarmycin B1, abbeymycin, anthramycin, centanamycin, chicamycin,mazethramycin, porothramycin A, porothramycin B, sibanomycin,sibiromycin, trabectedin, calicheamicin γ1, calicheamicin T, esperamicinA1, esperamicin C, esperamicin D, dynemicin A, dynemicin H, dynemicin M,dynemicin N, dynemicin O, dynemicin P, dynemicin Q, dynemicin S,neocarzinostatin chromophore, uncialamycin, 21-aminoepothilone B,eribulin, hemiasterlin, HTI-286, kahalatide F, elsamitrucin, lucanthone,melphalan, mitoguazone, nimustine, procarbazine, dacarbazine, amsacrine,5-amino-4-oxo-pentanoic acid, methyl 5-amino-4-oxo-pentanoate,actinomycin D, 7-aminoactinomycin D, bleomycin, mitomycin,staurosporine, desacetylvinblastine hydrazide, vinblastine, vincristine,vindesine, vinflunine, vinorelbine, afatinib, apilimod, balamapimod,barasertib, bosutinib, canertinib, cevipabulin, crizotinib, dacomitinib,dasatinib, denibulin, dilmapimod, dinaciclib, dovitinib, dutacatib,duvoglustat, edotecarin, elisidepsin, entinostat, epetirimod, erlotinib,fingolimod, fostamatinib, gefitinib, golotimod, gusperimus, imatinib,imiquimod, intedanib, ispinesib, lapatinib, lenalidomide, linifanib,litronesib, losmapimod, metesind, mocetinostat, motesanib, masitinib,myriocin, neratinib, nilotinib, odanacatib, ombrabulin, pamapimod,panobinostat, pazopanib, plerixafor, pomalidomide, razupenem,resiquimod, sabarubicin, saracatinib, seliciclib, selumetinib,sotirimod, squalamine, tacedinaline, talabostat, taltobulin, telatinib,tipifarnib, tozasertib, vandetanib, vatalanib, veliparib, voreloxin,alvespimycin, amikacin, amphotericin B, arbekacin, astromicin,bacitracin, balofloxacin, bederocin, bekanamycin, besifloxacin,brodimoprim, ciprofloxacin, clinafloxacin, colistin, daptomycin,dibekacin, enoxacin, framycetin, garenoxacin, gatifloxacin,gemifloxacin, gentamicin, gentamicin, grepafloxacin, hamycin,hexetidine, hygromycin B, ibacitabine, iclaprim, isepamicin,kanamycin,lomefloxacin, lucimycin, lymecycline, mepartricin, moxifloxacin,natamycin, nemonoxacin, neomycin B, neomycin C, netilmicin, norfloxacin,nystatin, omadacycline, oritavancin, paromomycin, pazufloxacin,perimycin A, perimycin B, perimycin C, pipemidic acid, polymyxin B,puromycin, radezolid, retaspimycin, ribostamycin, rimocidin, sisomicin,sitafloxacin, sparfloxacin, spectinomycin, streptomycin, sulfacetamide,sulfadiazine, sulfadimethoxine, sulfadimidine, sulfafurazole, sulfalene,sulfamazone, sulfamerazine, sulfamethizole, sulfamethoxazole,sulfamethoxypyridazine, sulfametomidine, sulfametoxydiazine,sulfametrole, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole,sulfapyridine, sulfathiazole, sulfathiourea, sulfisomidine, teicoplanin,telavancin, tanespimycin, temafloxacin, tetroxoprim, tigecycline,tobramycin, tosufloxacin, trimethoprim, trimethoprim, trovafloxacin,tyrothricin, ulifloxacin, valnemulin, vancomycin, verdamicin, andzabofloxacin. Other therapeutic agents having a primary amine groupand/or a secondary amine group are described in various compendia, suchas, for example, the Merck Index, 14th Edition, 2006; and the PhysiciansDesk Reference, 64th Edition, 2009.

An example of a therapeutic agent having at least one thiol group iscaptopril.

Examples of therapeutic agents having at least one hydroxy group includedoxorubicin and camptothecin.

Pharmaceutical Compositions Comprising Conjugates

Certain embodiments provided by the present disclosure relate topharmaceutical compositions, formulations, routes of administration anddoses of conjugates of Formula (II) or Formula (III).

Conjugates of Formula (II) or Formula (III) may be formulated with oneor more suitable pharmaceutically acceptable vehicles, diluents, and/orexcipients, which are well known, and can be determined, by one of skillin the art.

In certain embodiments, when the route of administration is parenteral(e.g. intravenous, intramuscular, intravenous, subcutaneous orinterperitoneal), the vehicle or excipient or excipient mixture can be asolvent or a dispersive medium containing, for example, various polar ornonpolar solvents, suitable mixtures thereof or oils. Examples ofvehicles or excipients include, but are not limited to, pharmaceuticallyacceptable solvents, dispersive agents or media, coatings, antimicrobialagents, iso- or hypo- or hypertonic agents, absorption modifying agents.Moreover, other or supplementary active ingredients can also beincorporated into the composition.

In certain embodiments, a pharmaceutical composition includes carriersand excipients such as buffers, carbohydrates, mannitol, proteins,polypeptides or amino acids such as glycine, antioxidants,bacteriostats, chelating agents, suspending agents, thickening agentsand/or preservatives, water, oils including but not limited to those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like, saline solutions,aqueous dextrose and glycerol solutions, flavoring agents, coloringagents, detackifiers and other acceptable additives, adjuvants, orbinders, other pharmaceutically acceptable auxiliary substances asrequired to approximate physiological conditions, such as pH bufferingagents, tonicity adjusting agents, emulsifying agents, wetting agentsand the like. Examples of excipients include, but are not limited to,starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. In certain embodiments, a pharmaceutical preparation issubstantially free of preservatives. In certain embodiments, apharmaceutical preparation contains at least one preservative.

Administration

In certain embodiments, conjugates of Formula (II) and Formula (III) maybe administered or applied singly, in combination with one or morepharmaceutically active agents, including another conjugate provided bythe present disclosure.

Conjugates of Formula (II) and Formula (III) and compositions thereofmay be administered by any appropriate route. In certain embodiments,conjugates of Formula (II) and Formula (III) and compositions thereofmay be administered parenterally, for example, by infusion or bolusinjection.

Dosage

Pharmaceutical compositions provided by the present disclosure comprisea conjugate of Formula (II) or Formula (III) and a pharmaceuticallyacceptable vehicle. In certain embodiments, a compound of Formula (II)or Formula (III) is present in a therapeutically effective amount, i.e.,in an amount effective to achieve therapeutic benefit in a patienthaving a cancer, an autoimmune disease, or an infectious disease. Theamount effective for a particular treatment will depend, at least inpart, on the disease or diseases being treated, the condition of thepatient, the severity of the disease, the formulation, and the route ofadministration, as well as other factors known to those of skill in theart. In vitro or in vivo assays can optionally be employed to helpidentify optimal doses and dosing regimens.

In certain embodiments, a therapeutically effective amount of aconjugate of Formula (II) or Formula (III) sufficient to treat a cancer,an autoimmune disease, or an infectious disease in a patient is fromabout 1 mg to about 10,000 mg of a conjugate of Formula (II) or Formula(III); in certain embodiments, from about 1 mg to about 5,000 mg; and incertain embodiments, from about 1 mg to about 1,000 mg of a conjugate ofFormula (II) or Formula (III).

Therapeutic Use

A conjugate of Formula (II), a conjugate of Formula (III), or apharmaceutical composition of any of the foregoing, can be administeredto a mammal, such as a human, to treat a cancer, an autoimmune disease,or an infectious disease.

In certain embodiments, methods of treating a cancer in a patientcomprise administering to a patient in need of such treatment aconjugate of Formula (II), a conjugate of Formula (III), or apharmaceutical composition of any of the foregoing, wherein D istherapeutically effective for treating the cancer. In certainembodiments, the cancer is selected from adrenal cortical cancer, analcancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer,bone metastasis, a brain cancer, a central nervous system (CNS) cancer,a peripheral nervous system (PNS) cancer, breast cancer, cervicalcancer, childhood Non-Hodgkin's lymphoma, colon and rectum cancer,endometrial cancer, esophagus cancer, Ewing's family of tumors, eyecancer, gallbladder cancer, a gastrointestinal carcinoid tumor, agastrointestinal stromal tumor, gestational trophoblastic disease, hairycell leukemia, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer,laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acutemyeloid leukemia, children's leukemia, chronic lymphocytic leukemia,chronic myeloid leukemia, liver cancer, lung cancer, a lung carcinoidtumor, Non-Hodgkin's lymphoma, male breast cancer, malignantmesothelioma, multiple myeloma, myelodysplastic syndrome,myeloproliferative disorders, nasal cavity and paranasal cancer,nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngealcancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer,pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma,salivary gland cancer, a sarcoma, melanoma skin cancer, non-melanomaskin cancers, stomach cancer, testicular cancer, thymus cancer, thyroidcancer, uterine cancer, transitional cell carcinoma, vaginal cancer,vulvar cancer, mesothelioma, squamous cell or epidermoid carcinoma,bronchial adenoma, choriocarcinoma, head and neck cancers,teratocarcinoma, and Waldenstrom's macroglobulinemia. In certainembodiments, the cancer is selected from acute lymphocytic leukemia,acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloidleukemia, multiple myeloma, breast cancer, prostate cancer, lung cancer,kidney cancer, liver cancer, and colon cancer.

In certain embodiments, methods of treating an autoimmune disease in apatient comprise administering to a patient in need of such treatment aconjugate of Formula (II), a conjugate of Formula (III), or apharmaceutical composition of any of the foregoing, wherein D istherapeutically effective for treating the autoimmune disease. Incertain embodiments, the autoimmune disease is selected from alopeciaareata, ankylosing spondylitis, Chagas disease, chronic obstructivepulmonary disease, Crohns Disease, dermatomyositis, diabetes mellitustype 1, endometriosis, Goodpasture's syndrome, Graves' disease,Guillain-Barré syndrome, Hashimoto's disease, Hidradenitis suppurativa,Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura,interstitial cystitis, lupus erythematosus, lupus nephritis, mixedconnective tissue disease, morphea, multiple sclerosis, Myastheniagravis, carcolepsy, meuromyotonia, Pemphigus vulgaris, Perniciousanaemia, psoriasis, psoriatic arthritis, polymyositis, primary biliarycirrhosis, relapsing polychondritis, rheumatoid arthritis, sarcoidosis,schizophrenia, scleroderma, Sjögren's syndrome, temporal arteritis,ulcerative colitis, vasculitis, and Wegener's granulomatosis. In certainembodiments, the autoimmune disease is selected from lupuserythematosus, psoriasis and multiple sclerosis. In certain embodiments,the autoimmune disease is multiple sclerosis and the multiple sclerosisis selected from relapsing remitting multiple sclerosis, secondaryprogressive multiple sclerosis, primary progressive multiple sclerosis,and progressive relapsing multiple sclerosis.

In certain embodiments, methods of treating an infectious disease in apatient comprise administering to a patient in need of such treatment aconjugate of Formula (II), a conjugate of Formula (III), or apharmaceutical composition of any of the foregoing, wherein D istherapeutically effective for treating the infectious disease. Incertain embodiments, the infectious disease is selected from a fungaldisease, a bacterial disease, and a viral disease. In certainembodiments, the infectious disease is a viral disease and the viraldisease is selected from Hepatitis A, Hepatitis B, Hepatitis C, andautoimmune deficiency disorder (AIDS).

In certain embodiments, a conjugate of Formula (II) or Formula (III) ora pharmaceutical composition of any of the foregoing may be administeredto a patient together with at least one second therapeutic agent. Incertain embodiments, the at least one second therapeutic agent isselected from an antitumor alkylating agent, an antitumorantimetabolite, an antitumor antibiotic, a plant-derived antitumoragent, an antitumor organoplatinum compound, an antitumor campthotecinderivative, an antitumor tyrosine kinase inhibitor, a monoclonalantibody, an interferon, a biological response modifier, a hormonalanti-tumor agent, an angiogenesis inhibitor, a differentiating agent,and a pharmaceutically acceptable salt of any of the foregoing. Incertain embodiments, the at least one second therapeutic agent isselected from paclitaxel, docetaxel, cyclophosphamide, ribavirin, andbortezomib.

A second therapeutic agent can be administered prior to, concomitantwith, or subsequent to administering a conjugate of Formula (II) orFormula (III) or pharmaceutical composition of any of the foregoing.

The conjugate compound of Formula (II) or Formula (III) can be cleavedunder mild basic conditions and/or by esterases in vivo to release thepharmaceutical agent. In certain embodiments, the conjugate Formula (II)or Formula (III) can release the pharmaceutical agent in vivo from aboutpH 7.4 to about pH 10, from about pH 7.4 to about pH 9.0, and in certainembodiments from about pH 7.4 to about pH 8.5.

EXAMPLES

The following examples describe in detail methods of synthesizingcrosslinkers, intermediates, and conjugates provided by the presentdisclosure, assays for characterizing crosslinkers and conjugatesprovided by the present disclosure, and methods of using crosslinkersand conjugates provided by the present disclosure. It will be apparentto those skilled in the art that many modifications, both to materialsand methods, may be practiced without departing from the scope of thedisclosure.

Example 1 Synthesis of Doxorubicin Conjugate (1)

A mixture of 1-chloromethyl chloroformate (1.0 eq) andtetrabutylammonium bisulfate (0.20 eq) in dichloromethane was cooled to0° C. with an ice-water bath. A 21% solution of sodium methanethiolate(1.0 eq) in water was added. The bilayer was stirred at 0° C. for 1 hand then at room temperature for 16 h. The reaction mixture was dilutedwith dichloromethane, washed with water, saturated bicarbonate solutionand brine, then dried over Na₂SO₄, filtered and concentrated in vacuo toprovide compound (1b) as a colorless liquid.

A mixture of 4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarboxylic acid(1c), compound (1b) (1.0 eq), and and triethylamine (1.0 eq) was stirredat 70° C. for 24 h. The reaction mixture was diluted with ethyl acetate,and washed with water, saturated bicarbonate solution and brine. Theorganic phase was separated, dried over Na₂SO₄, filtered andconcentrated in vacuo to yield the crude product. The crude material wasthen purified by silica gel column chromatography using ethyl acetateand hexanes to yield compound (1d).

To a solution of compound (1d) (1.0 eq) in dichloromethane (10 mL) wasadded N-hydroxysuccinimide (NHS) (3.0 eq) and the reaction mixturecooled to 0° C. A solution of 32% (v/v) peracetic acid in acetic acid(3.0 eq) was added dropwise over a period of 10 mins, and the solutionwas stirred at 0° C. for 3 h and then at room temperature overnight. Thereaction mixture was then diluted with dichloromethane and washed withwater, saturated sodium bicarbonate solution and brine, then dried overNa₂SO₄, filtered and concentrated in vacuo to give the crude product.The crude material was then purified by silica gel column chromatographyusing ethyl acetate and hexanes to yield compound (1e).

A mixture of compound (1e) (25.25 mg) and doxorubicin HCl (1.0 eq) andTEA (1.0 eq) in DMF (0.40 mL) was stirred at room temperature for 1 hand then concentrated under vacuum. The crude was purified byreverse-phase C-18 High Performance Liquid Chromatography (HPLC) usingacetonitrile/aqueous buffer as eluent to provide compound (1).

Example 2 Synthesis of Mitoxantrone Conjugate (2)

A mixture of compound (1e) (4.0 eq), mitoxantrone (1.0 eq), and TEA (5.0eq) in acetonitrile/aqueous buffer is stirred at room temperature for 3h and then concentrated under vacuum. The crude product is purified byreverse-phase C-18 High Performance Liquid Chromatography (HPLC) usingacetonitrile/aqueous buffer as eluent to provide compound (2).

Example 3 Synthesis of MPEG-maleimido-doxorubicin Conjugate (3)

A mixture of compound (1) and MPEG-SH (average MW 40K Daltons) inDMSO/aqueous buffer is stirred at room temperature for 1 h and thenconcentrated under vacuum. The crude product is purified usingsize-exclusion chromatography to provide compound (3).

Example 4 Synthesis of Boc-Cysteine-maleimido-doxorubicin Conjugate (4)

A mixture of compound (1) (5.81 mg) and Boc-cysteine (1.23 mg) inacetonitrile/aqueous potassium phosphate buffer (1.6 mL, pH 7.4) wasstirred at room temperature for 1 h to provide compound (4). Mass found:M+Na: 1080.

Example 5 Synthesis of L-Glutathione-maleimido-doxorubicin Conjugate (5)

A mixture of compound (1) (8.37 mg) and L-glutathione (reduced) (9.94mg) in acetonitrile/aqueous potassium phosphate buffer (2 mL, pH 7.4)was stirred at room temperature for 3 h to provide compound (5). Massfound: M+Na: 1167.

Example 6 Synthesis of Human Serum albumin-maleimido-doxorubicinConjugate (6)

A mixture of compound (1) and human serum albumin in DMSO/aqueouspotassium phosphate buffer was stirred at room temperature for 3 h toprovide compound (6).

Example 7 Chemical Stability

For chemical stability studies, buffers are prepared at pH 2.0, pH 7.4and pH 8.0. Compounds (1-500 μM) are incubated with buffers at 37° C.for 1 h in a temperature-controlled HPLC autosampler. Samples foranalysis are extracted at zero time and 1 h post-addition. Samples areanalyzed by HPLC, liquid chromatography-mass spectrometry (LC/MS), or byliquid chromatography-tandem mass spectrometry (LC/MS/MS).

Example 8 Metabolic Stability/Drug Release

Plasma Stability: Compounds (1-500 μM) are incubated with 10-100% mouse,rat or human serum or plasma at 37° C. for 1 hour to 10 days. Samplesare obtained at zero, 1 hour, and up to 10 days post-addition and areimmediately quenched with methanol or acetonitrile to prevent furtherconversion. Quenched samples are immediately analyzed or are frozen andmaintained at −80° C. prior to analysis. Samples are analyzed by LC,LC/MS or LC/MS/MS.

Compound 4 (5 μL of a 10 mM DMSO solution) was incubated with a 50% ratserum (Aleken Biologics) in potassium phosphate buffer (pH 7.4) solution(195 μL). After 1 hour, the sample was quenched with acetonitrile (600μL), centrifuged at 20,000×g, and the supernatant analyzed by LC at 220nm. The ratio of doxorubicin released to compound 4 was 10:90.

Liver Homogenate: Compounds (1-500 μM) are incubated with rat or humanliver S9 at 0.5 mg protein/mL in the presence of 1 mM NADPH at pH 7.4and at 37° C. for 1 hour to 10 days. Samples are obtained at zero, 1hour, and up to 10 days post-addition and are immediately quenched withmethanol or acetonitrile to prevent further conversion. Quenched samplesare immediately analyzed or are frozen and maintained at −80° C. priorto analysis. Samples are analyzed by LC, LC/MS or LC/MS/MS.

Caco-2 Cell Homogenate: Caco-2 cells are grown in flasks over 21 days.Cells are then rinsed/scraped into ice-cold 10 mM sodium phosphate/0.15M potassium chloride, pH 7.4. Cells are lysed by sonication at 4° C.using a probe sonicator and centrifuged at 9,000×g for 20 min at 4° C.Aliquots of the resulting supernatant (Caco-2 cell homogenate S9fraction) are transferred into 0.5 mL vials and stored at −80° C. priorto analysis. For stability studies, compounds (5 μM) are incubated withCaco-2 S9 (0.5 mg protein/mL) at pH 7.4 and 37° C. for 1 hour to 10days. Samples are obtained at zero, 1 hour, and up to 10 dayspost-addition and are immediately quenched with methanol or acetonitrileto prevent further conversion. Quenched samples are immediately analyzedor are frozen and maintained at −80° C. prior to analysis. Samples areanalyzed by LC, LC/MS or LC/MS/MS.

Pancreatin: Compounds (5 μM) are incubated with porcine pancreatin (10mg/mL in pH 7.5 buffer) at 37° C. for 24 hour. Samples are obtained atzero, 1 hour, and up to 10 days post-addition and are immediatelyquenched with methanol or acetonitrile to prevent further conversion.Quenched samples are immediately analyzed or are frozen and maintainedat −80° C. prior to analysis. Samples are analyzed by LC, LC/MS orLC/MS/MS.

Example 9 In Vitro Cytotoxicity

The effect of compounds provided by the present disclosure on cancercell growth and viability is measured in a panel of human cancer cellsgrown in vitro. All cancer cell lines are obtained, for example, fromthe American Tissue Type Collection (ATTC). Cells are maintained in thefollowing media: TUR, H69AR, Calu-6, ME180, and PC3 cells are grown inRPMI medium containing 4.5 g/L glucose, 10% FBS, 4 mM L-glutamine, and 1mM sodium pyruvate); and HT29 cells are grown in DMEM with 4.5 g/Lglucose, 10% FBS, and 6 mM/L-glutamine. All cells are grown at 37° C. in5% CO₂ and passaged bi-weekly.

For cytoxicity studies, cells are seeded into 96-well clear-bottommicrotiter plates at the following densities: TUR (7,500 cells/well),HT29 (5,000 cells/well), H69AR (10,000 cells/well), Calu-6 (15,000cells/well), and ME180 (2,500 cells/well). Cells are maintained at 37°C. with 5% CO₂ for 24 hours prior to addition of a test compound. Eachcondition is measured in triplicate. For compounds dissolved in DMSO,the final DMSO concentration in each well and in the non-drug treatedcontrol cells is constant and below 1% in all studies. The number ofviable cells is determined after 24, 48, and 72 hours using Alamar bluefluorescence. Briefly, Alamar blue (10 mM) is added to each well for 4hours, and the number of viable cells estimated by measuring thefluorescence of reduced Alamar blue (530 nm excitation, 590 nmemission). To correct for background fluorescence, cells are treatedwith 100% DMSO to eliminate all viable cells. The effect of a testcompound on cell growth is determined by calculating the fraction oflive cells treated with the test compound compared to untreated cells:(F1 drug treated—F1 DMSO killed)/(F1 untreated—F1 DMSO killed). The halfmaximal growth inhibition value (GI50) is calculated using commercialcurve-fitting software (e.g., Prism).

Example 10 Efficacy in Xenograph Model

Tumor xenograft studies are performed using nude athymic CD-1 mice (forexample, from Charles River Laboratories). Human cancer cells (5×10⁶PC3, 5×10⁶ HT29, 10⁷ Calu-6, and 5×10⁶ ME180) are implanted in the hindflank of nude mice. Tumor growth is measured using calipers and tumorvolume calculated using the formula: (width 2×(length/2)). Tumor volumeis measured 3 days per week. Animal weight is measured 3 days per weekto assess compound toxicity.

Compounds are tested for in vivo tumor growth inhibition as follows.Animals bearing tumors (100-200 mg) are sorted into groups (5-8 animals)with similar average tumor mass per group. Drug doses are administeredby intraperitoneal (IP) injection (0.5 mL). Test compounds are dissolvedin phosphate buffered saline (PBS) with the concentration adjusted foranimal weight. Actual drug concentrations in formulated doses areverified by quantitative nitrogen detection. Animals are dosed every 7days for 21 days in most studies. In several studies, animals are dosedtwice weekly (days 0, 4, 7, 10, 14, etc.). Tumor volume and animalweight are measured on days 0, 2, 4, 7, 9, 11, 14, 16, 18, 21, 23, 25,and 28. At the end of the study, animal blood is removed for analysis ofliver and kidney function (BUN, creatine, AST and ALT; analyticalmeasurements performed by Quality Clinical Labs). Tumor volume at theend of the study is calculated as a percentage of the tumor volume onday 0. The percent tumor growth inhibition is obtained from the ratio ofthe percentage tumor volume increase in drug treated animals to thepercentage tumor volume increase in saline treated animals.

Finally, it should be noted that there are alternative ways ofimplementing the disclosures contained herein. Accordingly, the presentembodiments are to be considered as illustrative and not restrictive,and the claims are not to be limited to the details given herein, butmay be modified within the scope and equivalents thereof.

1. A method of treating a patient suffering from a disease selected froma cancer, autoimmune disease, and infectious disease, comprisingadministering to a patient in need thereof a compound of Formula (II) ora pharmaceutically acceptable salt thereof:

wherein: each A¹ is independently a moiety selected from Formula (A¹a1),Formula (A¹a2), Formula (A¹a3), Formula (A¹b1), Formula (A¹b2), Formula(A¹c1), Formula (A¹c2), Formula (A¹c3), Formula (A¹d1), Formula (A¹d2),Formula (A¹d3), Formula (A¹e1), Formula (A¹f1), and Formula (A¹f2):

wherein: each R⁸ and R⁹ is independently selected from hydrogen, methyl,ethyl, n-propyl, isopropyl, phenyl, and benzyl; each E is selected fromF, Cl, Br, and I; and each L² is selected from halogen,N-hydroxysuccinimidyl, substituted N-hydroxysuccinimidyl, phenol-yl,substituted phenol-yl, hydroxybenzotriazolyl, substitutedhydroxybenzotriazolyl, imidazolyl, and substituted imidazolyl; each X¹and X³ is independently selected from a covalent bond, C₁₋₂₀ alkanediyl,substituted C₁₋₂₀ alkanediyl, C₁₋₂₀ heteroalkanediyl, substituted C₁₋₂₀heteroalkanediyl, C₃₋₁₂ cycloalkanediyl, substituted C₃₋₁₂cycloalkanediyl, C₃₋₁₂ heterocycloalkanediyl, substituted C₃₋₁₂heterocycloalkanediyl, C₄₋₂₀ alkanecycloalkanediyl, substituted C₄₋₂₀alkanecycloalkanediyl, C₄₋₂₀ heteroalkanecycloalkanediyl, substitutedC₄₋₂₀ heteroalkanecycloalkanediyl, C₆₋₂₀ arenediyl, substituted C₆₋₂₀arenediyl, C₆₋₂₀ heteroarenediyl, substituted C₆₋₂₀ heteroarenediyl,C₇₋₂₀ alkanearenediyl, substituted C₇₋₂₀ alkanearenediyl, C₆₋₂₀heteroalkanearenediyl, substituted C₆₋₂₀ heteroalkanearenediyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein: each n1 and n3 isindependently an integer selected from 0 to 5; and each n2 isindependently an integer selected from 1 to 25; each X² is independentlyselected from a covalent bond, —O—, —S—, —NH—, —N═, —N═N—, —N═CH—, —SO—,—SO₂—, —SO₂NH—, —SS—, —C(O)—, —C(O)O—, —C(O)NH—, —C(O)S—, —C(O)NH—N═,—OP(O)(OH)O—, —OC(O)O—, —OC(O)NH—, —NHC(O)NH—, and —NHC(S)NH—; each R¹and R² is independently selected from hydrogen, C₁₋₆ alkyl, substitutedC₁₋₆ alkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆ heteroalkyl, C₆₋₁₀ aryl,substituted C₆₋₁₀ aryl, C₆₋₁₀ heteroaryl, and substituted C₆₋₁₀heteroaryl; D is selected from aminopterin, folitixorin, methotrexate,pemetrexed, pralatrexate, raltitrexed, pelitrexol, talotrexin,deoxycoformycin, cladribine, clofarabine, fludarabine, thioguanine,mercaptopurine, berubicin, daunorubicin, doxorubicin, epirubicin,idarubicin, amrubicin, pirarubicin, zorubicin, mitoxantrone,banoxantrone, ledoxantrone, nortopixantrone, pixantrone, piroxantrone,sabarubicin, topixantrone, monomethyl auristatin E, monomethylauristatin F, monomethyl dolastatin 10, dolastatin 15, belotecan,atiratecan, camptothecin, exatecan, irinotecan, namitecan, rubitecan,topotecan, demecolcine, duocarmycin A, duocarmycin SA, duocarmycin B,duocarmycin B1, abbeymycin, anthramycin, centanamycin, chicamycin,mazethramycin, porothramycin A, porothramycin B, sibanomycin,sibiromycin, trabectedin, calicheamicin γ1, calicheamicin T, esperamicinA1, esperamicin C, esperamicin D, dynemicin A, dynemicin H, dynemicin M,dynemicin N, dynemicin O, dynemicin P, dynemicin Q, dynemicin S,neocarzinostatin chromophore, uncialamycin, 21-aminoepothilone B,eribulin, hemiasterlin, HTI-286, kahalatide F, elsamitrucin, lucanthone,melphalan, mitoguazone, nimustine, procarbazine, dacarbazine, amsacrine,5-amino-4-oxo-pentanoic acid, methyl 5-amino-4-oxo-pentanoate,actinomycin D, 7-aminoactinomycin D, bleomycin, mitomycin,staurosporine, desacetylvinblastine hydrazide, vinblastine, vincristine,vindesine, vinflunine, vinorelbine, afatinib, apilimod, balamapimod,barasertib, bosutinib, canertinib, cevipabulin, crizotinib, dacomitinib,dasatinib, denibulin, dilmapimod, dinaciclib, dovitinib, dutacatib,duvoglustat, edotecarin, elisidepsin, entinostat, epetirimod, erlotinib,fingolimod, fostamatinib, gefitinib, golotimod, gusperimus, imatinib,imiquimod, intedanib, ispinesib, lapatinib, lenalidomide, linifanib,litronesib, losmapimod, metesind, mocetinostat, motesanib, masitinib,myriocin, neratinib, nilotinib, odanacatib, ombrabulin, pamapimod,panobinostat, pazopanib, plerixafor, pomalidomide, razupenem,resiquimod, sabarubicin, saracatinib, seliciclib, selumetinib,sotirimod, squalamine, tacedinaline, talabostat, taltobulin, telatinib,tipifarnib, tozasertib, vandetanib, vatalanib, veliparib, voreloxin,alvespimycin, amikacin, amphotericin B, arbekacin, astromicin,bacitracin, balofloxacin, bederocin, bekanamycin, besifloxacin,brodimoprim, ciprofloxacin, clinafloxacin, colistin, daptomycin,dibekacin, enoxacin, framycetin, garenoxacin, gatifloxacin,gemifloxacin, gentamicin, gentamicin, grepafloxacin, hamycin,hexetidine, hygromycin B, ibacitabine, iclaprim, isepamicin, kanamycin,lomefloxacin, lucimycin, lymecycline, mepartricin, moxifloxacin,natamycin, nemonoxacin, neomycin B, neomycin C, netilmicin, norfloxacin,nystatin, omadacycline, oritavancin, paromomycin, pazufloxacin,perimycin A, perimycin B, perimycin C, pipemidic acid, polymyxin B,puromycin, radezolid, retaspimycin, ribostamycin, rimocidin, sisomicin,sitafloxacin, sparfloxacin, spectinomycin, streptomycin, sulfacetamide,sulfadiazine, sulfadimethoxine, sulfadimidine, sulfafurazole, sulfalene,sulfamazone, sulfamerazine, sulfamethizole, sulfamethoxazole,sulfamethoxypyridazine, sulfametomidine, sulfametoxydiazine,sulfametrole, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole,sulfapyridine, sulfathiazole, sulfathiourea, sulfisomidine, teicoplanin,telavancin, tanespimycin, temafloxacin, tetroxoprim, tigecycline,tobramycin, tosufloxacin, trimethoprim, trimethoprim, trovafloxacin,tyrothricin, ulifloxacin, valnemulin, vancomycin, verdamicin, andzabofloxacin; and n5 is an integer selected from 1 to
 20. 2. The methodof claim 1, wherein the cancer is selected from adrenal cortical cancer,anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bonecancer, bone metastasis, a brain cancer, a central nervous system (CNS)cancer, a peripheral nervous system (PNS) cancer, breast cancer,cervical cancer, childhood Non-Hodgkin's lymphoma, colon and rectumcancer, endometrial cancer, esophagus cancer, Ewing's family of tumors,eye cancer, gallbladder cancer, a gastrointestinal carcinoid tumor, agastrointestinal stromal tumor, gestational trophoblastic disease, hairycell leukemia, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer,laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acutemyeloid leukemia, children's leukemia, chronic lymphocytic leukemia,chronic myeloid leukemia, liver cancer, lung cancer, a lung carcinoidtumor, Non-Hodgkin's lymphoma, male breast cancer, malignantmesothelioma, multiple myeloma, myelodysplastic syndrome,myeloproliferative disorders, nasal cavity and paranasal cancer,nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngealcancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer,pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma,salivary gland cancer, a sarcoma, melanoma skin cancer, non-melanomaskin cancers, stomach cancer, testicular cancer, thymus cancer, thyroidcancer, uterine cancer, transitional cell carcinoma, vaginal cancer,vulvar cancer, mesothelioma, squamous cell or epidermoid carcinoma,bronchial adenoma, choriocarcinoma, head and neck cancers,teratocarcinoma, and Waldenstrom's macroglobulinemia.
 3. The method ofclaim 1, wherein the autoimmune disease is selected from alopeciaareata, ankylosing spondylitis, Chagas disease, chronic obstructivepulmonary disease, Crohns Disease, dermatomyositis, diabetes mellitustype 1, endometriosis, Goodpasture's syndrome, Graves' disease,Guillain-Barré syndrome, Hashimoto's disease, Hidradenitis suppurativa,Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura,interstitial cystitis, lupus erythematosus, lupus nephritis, mixedconnective tissue disease, morphea, multiple sclerosis, Myastheniagravis, carcolepsy, meuromyotonia, Pemphigus vulgaris, Perniciousanaemia, psoriasis, psoriatic arthritis, polymyositis, primary biliarycirrhosis, relapsing polychondritis, rheumatoid arthritis, sarcoidosis,schizophrenia, scleroderma, Sjögren's syndrome, temporal arteritis,ulcerative colitis, vasculitis, and Wegener's granulomatosis.
 4. Themethod of claim 1, wherein the infectious disease is selected from afungal disease, a bacterial disease, and a viral disease.
 5. The methodof claim 1 comprising administering a second therapeutic agent effectivein treating a cancer, autoimmune disease, or infectious disease.
 6. Themethod of claim 1, wherein each A¹ is independently a moiety selectedfrom Formula (A¹a1a), Formula (A¹a2a), Formula (A¹a2b), Formula (A¹a3a),Formula (A¹a3b), Formula (A¹b1a), Formula (A¹b1b), Formula (A¹b1c),Formula (A¹b2a), Formula (A¹b2b), Formula (A¹b2c), Formula (A¹c1),Formula (A¹c2), Formula (A¹c3), Formula (A¹d1), Formula (A¹d2), Formula(A¹d3), Formula (A¹e1), Formula (A¹f1), and Formula (A¹f2):


7. The method of claim 1, wherein each X¹ and X³ is independentlyselected from a covalent bond, C₁₋₂₀ alkanediyl, C₁₋₂₀ cycloalkanediyl,C₆₋₁₀ arenediyl, C₇₋₂₀ alkanearenediyl, and—(CH₂)_(n1)—(CH₂—CH₂—O)_(n2)—(CH₂)_(n3)—, wherein each n1 and n3 isindependently an integer selected from 0 to 5 and each n2 isindependently an integer selected from 1 to
 25. 8. The compound of claim1, wherein each X¹ and X³ is independently selected from a covalentbond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl, hexane-1,6-diyl, benzene-diyl, methylbenzene-diyl,ethylbenzene-diyl, propylbenzene-diyl, methyl cyclohexane-diyl,—(CH₂)₂—(CH₂—CH₂—O)(CH₂)—, —(CH₂)₂—(CH₂—CH₂O)₂—(CH₂)—, and—(CH₂)₂—(CH₂—CH₂O)₃—(CH₂)₂—.
 9. The compound of claim 1, wherein each X²is selected from a covalent bond, —O—, —S—, —SO—, —SO₂—, —SO₂NH—, —SS—,—C(O)—, —C(O)O—, —C(O)NH—, —C(O)NH—N═, —OC(O)NH—, and —NHC(O)NH—. 10.The method of claim 1, wherein each X² is selected from a covalent bond,—O—, —SO₂NH—, —SS—, —C(O)—, —C(O)O—, and —C(O)NH—.
 11. The method ofclaim 1, wherein each R¹ and R² is independently selected from hydrogen,methyl, ethyl, propyl, isopropyl, and phenyl.
 12. The method of claim 1,wherein the compound is selected from the compound of Formula (II-A-1),Formula (II-A-2), Formula (II-A-3), Formula (II-A-4), Formula (II-A-5),Formula (II-A-6), Formula (II-A-7), Formula (II-A-8), Formula (II-A-9),and Formula (II-A-10):


13. The compound of claim 1, wherein the compound is selected from thecompound of Formula (II-B-1), Formula (II-B-2), Formula (II-B-3),Formula (II-B-4), Formula (II-B-5), Formula (II-B-6), Formula (II-B-7),Formula (II-B-8), Formula (II-B-9), Formula (II-B-10), Formula(II-B-11), Formula (II-B-12), and Formula (II-B-13):


14. The compound of claim 1, wherein the compound is selected fromFormula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula(II-e), Formula (II-f), Formula (II-g), Formula (II-h), Formula (II-i),Formula (II j), Formula (II-k), Formula (II-l), Formula (II-m), Formula(II-n), Formula (II-o), Formula (II-p), Formula (II-q), Formula (II-r),Formula (II-s), Formula (II-t), Formula (II-u), Formula (II-v), Formula(II-w), Formula (II-x), Formula (II-y), Formula (II-z), Formula (II-aa),Formula (II-ab), and Formula (II-ac), or a salt of any of the foregoing: